Information

20.12: Transduction of Light - Biology


The rods and cones are the site of transduction of light to a neural signal. In vertebrates, the main photopigment, rhodopsin, has two main parts Figure 1): an opsin, which is a membrane protein (in the form of a cluster of α-helices that span the membrane), and retinal—a molecule that absorbs light.

When light hits a photoreceptor, it causes a shape change in the retinal, altering its structure from a bent (cis) form of the molecule to its linear (trans) isomer. This isomerization of retinal activates the rhodopsin, starting a cascade of events that ends with the closing of Na+ channels in the membrane of the photoreceptor. Thus, unlike most other sensory neurons (which become depolarized by exposure to a stimulus) visual receptors become hyperpolarized and thus driven away from threshold (Figure 2).

Trichromatic Coding

There are three types of cones (with different photopsins), and they differ in the wavelength to which they are most responsive, as shown in Figure 3. Some cones are maximally responsive to short light waves of 420 nm, so they are called S cones (“S” for “short”); others respond maximally to waves of 530 nm (M cones, for “medium”); a third group responds maximally to light of longer wavelengths, at 560 nm (L, or “long” cones). With only one type of cone, color vision would not be possible, and a two-cone (dichromatic) system has limitations. Primates use a three-cone (trichromatic) system, resulting in full color vision.

The color we perceive is a result of the ratio of activity of our three types of cones. The colors of the visual spectrum, running from long-wavelength light to short, are red (700 nm), orange (600 nm), yellow (565 nm), green (497 nm), blue (470 nm), indigo (450 nm), and violet (425 nm). Humans have very sensitive perception of color and can distinguish about 500 levels of brightness, 200 different hues, and 20 steps of saturation, or about 2 million distinct colors.

Retinal Processing

Visual signals leave the cones and rods, travel to the bipolar cells, and then to ganglion cells. A large degree of processing of visual information occurs in the retina itself, before visual information is sent to the brain.

Photoreceptors in the retina continuously undergo tonic activity. That is, they are always slightly active even when not stimulated by light. In neurons that exhibit tonic activity, the absence of stimuli maintains a firing rate at a baseline; while some stimuli increase firing rate from the baseline, and other stimuli decrease firing rate. In the absence of light, the bipolar neurons that connect rods and cones to ganglion cells are continuously and actively inhibited by the rods and cones. Exposure of the retina to light hyperpolarizes the rods and cones and removes their inhibition of bipolar cells. The now active bipolar cells in turn stimulate the ganglion cells, which send action potentials along their axons (which leave the eye as the optic nerve). Thus, the visual system relies on change in retinal activity, rather than the absence or presence of activity, to encode visual signals for the brain. Sometimes horizontal cells carry signals from one rod or cone to other photoreceptors and to several bipolar cells. When a rod or cone stimulates a horizontal cell, the horizontal cell inhibits more distant photoreceptors and bipolar cells, creating lateral inhibition. This inhibition sharpens edges and enhances contrast in the images by making regions receiving light appear lighter and dark surroundings appear darker. Amacrine cells can distribute information from one bipolar cell to many ganglion cells.

You can demonstrate this using an easy demonstration to “trick” your retina and brain about the colors you are observing in your visual field. Look fixedly at Figure 4 for about 45 seconds. Then quickly shift your gaze to a sheet of blank white paper or a white wall. You should see an afterimage of the Norwegian flag in its correct colors. At this point, close your eyes for a moment, then reopen them, looking again at the white paper or wall; the afterimage of the flag should continue to appear as red, white, and blue.

What causes this? According to an explanation called opponent process theory, as you gazed fixedly at the green, black, and yellow flag, your retinal ganglion cells that respond positively to green, black, and yellow increased their firing dramatically. When you shifted your gaze to the neutral white ground, these ganglion cells abruptly decreased their activity and the brain interpreted this abrupt downshift as if the ganglion cells were responding now to their “opponent” colors: red, white, and blue, respectively, in the visual field. Once the ganglion cells return to their baseline activity state, the false perception of color will disappear.


20.12: Transduction of Light - Biology

Light is composed of photons that make up electromagnetic waves, which are characterized by wavelength, frequency, and amplitude.

Learning Objectives

Describe the characteristics of light

Key Takeaways

Key Points

  • Light is composed of electromagnetic waves that can travel without a medium, unlike sound.
  • The behavior of light can be seen in the behavior of waves and photons, the basic unit of light.
  • A wavelength (which varies inversely with frequency ) manifests itself as color, while wave amplitude is perceived as luminous intensity or brightness it is measured by the standard unit of a candela.
  • Humans can see light that ranges between 380 nm and 740 nm, but cannot see light that is below the frequency of visible red light or above the frequency of visible violet light.
  • Light at the red end of the visible spectrum has long wavelengths (and is lower frequency), while light at the violet end has short wavelengths (and is higher frequency).
  • Light waves enter the eye as long (red), medium (green), and short (blue) waves the color of an object is the color the object reflects.

Key Terms

  • photon: the quantum of light and other electromagnetic energy, regarded as a discrete particle having zero rest mass, no electric charge, and an indefinitely long lifetime
  • nanometer: one billionth of a meter used to express wavelength of light
  • electromagnetic spectrum: the entire range of wavelengths of all known radiations consisting of oscillating electric and magnetic fields, including gamma rays, visible light, infrared, radio waves, and X-rays
  • wavelength: the length of a single cycle of a wave, as measured by the distance between one peak or trough of a wave and the next it corresponds to the velocity of the wave divided by its frequency

Light

As with auditory stimuli, light travels in waves. While the compression waves that compose sound must travel in a medium (consisting of a gas, a liquid, or a solid), light is composed of electromagnetic waves and needs no medium. Light can, in fact, travel in a vacuum. The behavior of light can be described in terms of the behavior of waves and the behavior of the fundamental unit of light, the photon: a packet of electromagnetic radiation. A glance at the electromagnetic spectrum shows that visible light for humans is just a small slice of the entire spectrum, which includes radiation that we cannot see as light because it is below the frequency of visible red light and above the frequency of visible violet light.

Electromagnetic spectrum: A glance at the electromagnetic spectrum shows that visible light for humans is just a small slice of the entire spectrum.

Certain variables are important when discussing perception of light. A wavelength (which varies inversely with frequency) manifests itself as color. Light at the red end of the visible spectrum has longer wavelengths (and is lower frequency), while light at the violet end has shorter wavelengths (and is higher frequency). The wavelength of light is expressed in nanometers (nm) one nanometer is one billionth of a meter. Humans perceive light that ranges between approximately 380 nm and 740 nm. However, some other animals can detect wavelengths outside of the human range. For example, bees see near-ultraviolet light in order to locate nectar guides on flowers. Some non-avian reptiles sense infrared light (such as heat that prey gives off).

Wave amplitude is perceived as luminous intensity or brightness. The standard unit of intensity of light is the candela, which is approximately the luminous intensity of one common candle.

Light waves travel 299,792 km per second in a vacuum and somewhat slower in various media such as air and water. Those waves arrive at the eye as long (red), medium (green), and short (blue) waves. The term “white light” is light that is perceived as white by the human eye. This effect is produced by light that stimulates the color receptors in the human eye equally. The apparent color of an object is actually the color (or colors) the object reflects. Thus a red object reflects the red wavelengths in mixed (white) light and absorbs all other wavelengths of light.


Higher Processing

The inner hair cells are most important for conveying auditory information to the brain. About 90 percent of the afferent neurons carry information from inner hair cells, with each hair cell synapsing with 10 or so neurons. Outer hair cells connect to only 10 percent of the afferent neurons, and each afferent neuron innervates many hair cells. The afferent, bipolar neurons that convey auditory information travel from the cochlea to the medulla, through the pons and midbrain in the brainstem, finally reaching the primary auditory cortex in the temporal lobe.


LABORATORY OF PLANT MOLECULAR BIOLOGY

Light signal transduction pathways are central to the regulation of plant development. They enable information regarding the intensity and duration of specific wavelengths of light to be amplified and coordinated, resulting in complex physiological and developmental responses throughout the life cycle (e.g. germination, seedling de-etiolation, neighbor avoidance and flowering). Plants perceive discrete wavelengths of light through photoreceptors, such as the red/far-red light-sensing phytochromes and the blue light-sensing cryptochromes.

The dramatic switch from skotomorphogenic (etiolated) seedling development to photomorphogenic (de-etiolated) development provides an excellent system to elucidate light signal transduction cascades in plants. Genetic screens of mutagenized seedling populations have identified both positively acting components (receptors, signaling intermediates) and repressors of photomorphogenesis. Our laboratory has focused in particular on identifying intermediates that promote phytochome A signal transduction. Mutant screens identified p hytochrome A signal t ransmission (pat) and l ong a fter f ar-red (laf) mutants. Characterization of these mutants has enabled identification of novel intermediates required for complete responsiveness to activated phytochrome A.

Others have identified four biochemical entities: COP1, the CSN, COP10 and DET1 that repress photomorphogenesis in darkness. Characterization of COP1, the CSN and COP10 strongly suggests that ubiquitin-mediated proteolysis plays a critical role in the elimination of signaling components that enable skotomorphogenesis so that they can be replaced by a signaling network that promotes photomorphogenesis. However, the phenotypes of mutants defective in COP gene products indicate that they transduce not only signals from multiple photoreceptors but apparently play central roles in the transduction of signals not directly related to the perception of light.

COP1 is one of approximately 400 Arabidopsis proteins that bear a RING motif. This arrangement of eight cysteine and histidine residues that coordinate two zinc ions is a distinctive feature of a class of E3 proteins. We were the first to demonstrate E3 activity of COP1 and have shown that COP1 plays an important role in phytochrome A signal desensitization via degradation of LAF1, a transcription factor that is required for full response capacity to activated phytochrome A. The demonstration by others that COP1 interacts with a negative repressor of phytochrome A named SPA1 prompted us to test the effect of SPA1 on COP1-mediated ubiquitination. The coiled-coil domain of SPA1 promotes LAF1 ubiquitination, but only at low COP1 concentrations. Based on current insight into the role of nuclear depletion of COP1 after irradiation, this observation suggests a mechanism whereby COP1 in de-etiolated seedlings might act selectively on different substrates to ensure the attenuation of light signals transduced from a specific photoreceptor.

Zhou Q, Hare PD, Yang SW, Zeidler M, Huang L-F, Chua, N-H (2005) FHL is required for full phytochrome A signaling and shares overlapping functions with FHY1. Plant J 43: 356-370

Jang I-C, Yang J-Y, Seo HS, Chua N-H (2005) HFR1 is targeted by COP1 E3 ligase for post-translational proteolysis during phytochrome A signaling. Genes Dev 19:593-602

Zeidler M, Zhou Q, Sarda, Yau C-P, Chua N-H (2004) The nuclear localization signal and the C-terminal region of FHY1 are required for transmission of phytochrome A signals. Plant J 40:355-36

Seo HS, Watanabe E, Tokutomi S, Nagatani A, Chua NH (2004) Photoreceptor ubiquitination by COP1 E3 ligase desensitizes phytochrome A signaling. Genes Dev 18:617-622

Seo HS, Yang JY, Ishikawa M, Bolle C, Ballesteros ML, Chua NH (2003) LAF1 ubiquitination by COP1 controls photomorphogenesis and is stimulated by SPA1. Nature 423:995-999

Moller SG, Kim YS, Kunkel T, Chua NH (2003) PP7 is a positive regulator of blue light signaling in Arabidopsis. Plant Cell 15:1111-1119

Hare PD, Moller SG, Huang L-F, Chua NH (2003) LAF3, a novel factor required for normal phytochrome A signaling. Plant Physiol 133: 1592-1604

Ballesteros ML, Bolle C, Lois LM, Moore JM, Vielle-Calzada JP, Grossniklaus U, Chua NH (2001) LAF1, a MYB transcription activator for phytochrome A signaling. Genes Dev 15: 2613-2625

Moller SG, Kunkel T, Chua NH (2001) A plastidic ABC protein involved in intercompartmental communication of light signaling. Genes Dev 15:90-103

Zeidler M, Bolle C, Chua NH (2001) The phytochrome a specific signaling component PAT3 is a positive regulator of arabidopsis photomorphogenesis. Plant Cell Physiol 42:1193-1200

Bolle C, Koncz C, Chua NH (2000) PAT1, a new member of the GRAS family, is involved in phytochrome A signal transduction. Genes Dev 14:1269-1278

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Rod and cone cells

Human rod cells and the different types of cone cells each have an optimal wavelength. However, there is considerable overlap in the wavelengths of light detected.

The color we perceive is a result of the ratio of activity of our three types of cones. The colors of the visual spectrum, running from long-wavelength light to short are:

  • red (700 nm)
  • orange (600 nm)
  • yellow (565 nm)
  • green (497 nm)
  • blue (470 nm)
  • indigo (450 nm)
  • violet (425 nm).

Humans have very sensitive perception of color and can distinguish about 500 levels of brightness, 200 different hues, and 20 steps of saturation in all, about 2 million distinct colors.


Contents

The basis for signal transduction is the transformation of a certain stimulus into a biochemical signal. The nature of such stimuli can vary widely, ranging from extracellular cues, such as the presence of EGF, to intracellular events, such as the DNA damage resulting from replicative telomere attrition. [7] Traditionally, signals that reach the central nervous system are classified as senses. These are transmitted from neuron to neuron in a process called synaptic transmission. Many other intercellular signal relay mechanisms exist in multicellular organisms, such as those that govern embryonic development. [8]

Ligands Edit

The majority of signal transduction pathways involve the binding of signaling molecules, known as ligands, to receptors that trigger events inside the cell. The binding of a signaling molecule with a receptor causes a change in the conformation of the receptor, known as receptor activation. Most ligands are soluble molecules from the extracellular medium which bind to cell surface receptors. These include growth factors, cytokines and neurotransmitters. Components of the extracellular matrix such as fibronectin and hyaluronan can also bind to such receptors (integrins and CD44, respectively). In addition, some molecules such as steroid hormones are lipid-soluble and thus cross the plasma membrane to reach nuclear receptors. [9] In the case of steroid hormone receptors, their stimulation leads to binding to the promoter region of steroid-responsive genes. [10]

Not all classifications of signaling molecules take into account the molecular nature of each class member. For example, odorants belong to a wide range of molecular classes, [11] as do neurotransmitters, which range in size from small molecules such as dopamine [12] to neuropeptides such as endorphins. [13] Moreover, some molecules may fit into more than one class, e.g. epinephrine is a neurotransmitter when secreted by the central nervous system and a hormone when secreted by the adrenal medulla.

Some receptors such as HER2 are capable of ligand-independent activation when overexpressed or mutated. This leads to constituitive activation of the pathway, which may or may not be overturned by compensation mechanisms. In the case of HER2, which acts as a dimerization partner of other EGFRs, constituitive activation leads to hyperproliferation and cancer. [14]

Mechanical forces Edit

The prevalence of basement membranes in the tissues of Eumetazoans means that most cell types require attachment to survive. This requirement has led to the development of complex mechanotransduction pathways, allowing cells to sense the stiffness of the substratum. Such signaling is mainly orchestrated in focal adhesions, regions where the integrin-bound actin cytoskeleton detects changes and transmits them downstream through YAP1. [15] Calcium-dependent cell adhesion molecules such as cadherins and selectins can also mediate mechanotransduction. [16] Specialised forms of mechanotransduction within the nervous system are responsible for mechanosensation: hearing, touch, proprioception and balance. [17]

Osmolarity Edit

Cellular and systemic control of osmotic pressure (the difference in osmolarity between the cytosol and the extracellular medium) is critical for homeostasis. There are three ways in which cells can detect osmotic stimuli: as changes in macromolecular crowding, ionic strength, and changes in the properties of the plasma membrane or cytoskeleton (the latter being a form of mechanotransduction). [18] These changes are detected by proteins known as osmosensors or osmoreceptors. In humans, the best characterised osmosensors are transient receptor potential channels present in the primary cilium of human cells. [18] [19] In yeast, the HOG pathway has been extensively characterised. [20]

Temperature Edit

The sensing of temperature in cells is known as thermoception and is primarily mediated by transient receptor potential channels. [21] Additionally, animal cells contain a conserved mechanism to prevent high temperatures from causing cellular damage, the heat-shock response. Such response is triggered when high temperatures cause the dissociation of inactive HSF1 from complexes with heat shock proteins Hsp40/Hsp70 and Hsp90. With help from the ncRNA hsr1, HSF1 then trimerizes, becoming active and upregulating the expression of its target genes. [22] Many other thermosensory mechanisms exist in both prokaryotes and eukaryotes. [21]

Light Edit

In mammals, light controls the sense of sight and the circadian clock by activating light-sensitive proteins in photoreceptor cells in the eye's retina. In the case of vision, light is detected by rhodopsin in rod and cone cells. [23] In the case of the circadian clock, a different photopigment, melanopsin, is responsible for detecting light in intrinsically photosensitive retinal ganglion cells. [24]

Receptors can be roughly divided into two major classes: intracellular and extracellular receptors.

Extracellular receptors Edit

Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside region of the receptor (the ligand does not pass through the membrane). Ligand-receptor binding induces a change in the conformation of the inside part of the receptor, a process sometimes called "receptor activation". [25] This results in either the activation of an enzyme domain of the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.

In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity examples include tyrosine kinase and phosphatases. Often such enzymes are covalently linked to the receptor. Some of them create second messengers such as cyclic AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with adaptor proteins that facilitate signaling protein interactions and coordination of signaling complexes necessary to respond to a particular stimulus. Enzymes and adaptor proteins are both responsive to various second messenger molecules.

Many adaptor proteins and enzymes activated as part of signal transduction possess specialized protein domains that bind to specific secondary messenger molecules. For example, calcium ions bind to the EF hand domains of calmodulin, allowing it to bind and activate calmodulin-dependent kinase. PIP3 and other phosphoinositides do the same thing to the Pleckstrin homology domains of proteins such as the kinase protein AKT.

G protein–coupled receptors Edit

G protein–coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimeric G protein. With nearly 800 members, this is the largest family of membrane proteins and receptors in mammals. Counting all animal species, they add up to over 5000. [26] Mammalian GPCRs are classified into 5 major families: rhodopsin-like, secretin-like, metabotropic glutamate, adhesion and frizzled/smoothened, with a few GPCR groups being difficult to classify due to low sequence similarity, e.g. vomeronasal receptors. [26] Other classes exist in eukaryotes, such as the Dictyostelium cyclic AMP receptors and fungal mating pheromone receptors. [26]

Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor the G protein exists as a heterotrimer consisting of Gα, Gβ, and Gγ subunits. [27] Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits. The dissociation exposes sites on the subunits that can interact with other molecules. [28] The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such as phospholipases and ion channels, the latter permitting the release of second messenger molecules. [29] The total strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic enzymatic activity e.g. via protein kinase phosphorylation or b-arrestin-dependent internalization.

A study was conducted where a point mutation was inserted into the gene encoding the chemokine receptor CXCR2 mutated cells underwent a malignant transformation due to the expression of CXCR2 in an active conformation despite the absence of chemokine-binding. This meant that chemokine receptors can contribute to cancer development. [30]

Tyrosine, Ser/Thr and Histidine-specific protein kinases Edit

Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligands examples include growth factor receptors such as the insulin receptor. [31] To perform signal transduction, RTKs need to form dimers in the plasma membrane [32] the dimer is stabilized by ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the autophosphorylation of tyrosine residues within the intracellular kinase domains of the RTKs, causing conformational changes. Subsequent to this, the receptors' kinase domains are activated, initiating phosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as cell differentiation and metabolism. [31] Many Ser/Thr and dual-specificity protein kinases are important for signal transduction, either acting downstream of [receptor tyrosine kinases], or as membrane-embedded or cell-soluble versions in their own right. The process of signal transduction involves around 560 known protein kinases and pseudokinases, encoded by the human kinome [33] [34]

As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK into the cell. In this case, the G proteins are members of the Ras, Rho, and Raf families, referred to collectively as small G proteins. They act as molecular switches usually tethered to membranes by isoprenyl groups linked to their carboxyl ends. Upon activation, they assign proteins to specific membrane subdomains where they participate in signaling. Activated RTKs in turn activate small G proteins that activate guanine nucleotide exchange factors such as SOS1. Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor's initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors that exist in a constitutively activated state such mutated genes may act as oncogenes. [35]

Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes, fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a different protein or the kinase itself, thus activating the aspartate residue. [36]

Integrins Edit

Integrins are produced by a wide variety of cells they play a role in cell attachment to other cells and the extracellular matrix and in the transduction of signals from extracellular matrix components such as fibronectin and collagen. Ligand binding to the extracellular domain of integrins changes the protein's conformation, clustering it at the cell membrane to initiate signal transduction. Integrins lack kinase activity hence, integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator being integrin-linked kinase. [37] As shown in the adjacent picture, cooperative integrin-RTK signaling determines the timing of cellular survival, apoptosis, proliferation, and differentiation.

Important differences exist between integrin-signaling in circulating blood cells and non-circulating cells such as epithelial cells integrins of circulating cells are normally inactive. For example, cell membrane integrins on circulating leukocytes are maintained in an inactive state to avoid epithelial cell attachment they are activated only in response to stimuli such as those received at the site of an inflammatory response. In a similar manner, integrins at the cell membrane of circulating platelets are normally kept inactive to avoid thrombosis. Epithelial cells (which are non-circulating) normally have active integrins at their cell membrane, helping maintain their stable adhesion to underlying stromal cells that provide signals to maintain normal functioning. [38]

In plants, there are no bona fide integrin receptors identified to date nevertheless, several integrin-like proteins were proposed based on structural homology with the metazoan receptors. [39] Plants contain integrin-linked kinases that are very similar in their primary structure with the animal ILKs. In the experimental model plant Arabidopsis thaliana, one of the integrin-linked kinase genes, ILK1, has been shown to be a critical element in the plant immune response to signal molecules from bacterial pathogens and plant sensitivity to salt and osmotic stress. [40] ILK1 protein interacts with the high-affinity potassium transporter HAK5 and with the calcium sensor CML9. [40] [41]

Toll-like receptors Edit

When activated, toll-like receptors (TLRs) take adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adaptor molecules are known to be involved in signaling, which are Myd88, TIRAP, TRIF, and TRAM. [42] [43] [44] These adapters activate other intracellular molecules such as IRAK1, IRAK4, TBK1, and IKKi that amplify the signal, eventually leading to the induction or suppression of genes that cause certain responses. Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for gene modulation.

Ligand-gated ion channels Edit

A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell membrane through which ions relaying signals can pass. An example of this mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in response to the opening of these channels induces action potentials, such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of voltage-gated ion channels.

An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca 2+ it acts as a second messenger initiating signal transduction cascades and altering the physiology of the responding cell. This results in amplification of the synapse response between synaptic cells by remodelling the dendritic spines involved in the synapse.

Intracellular receptors Edit

Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are non-polar hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, altering gene expression.

Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Due to their enabling gene transcription, they are alternatively called inductors of gene expression. All hormones that act by regulation of gene expression have two consequences in their mechanism of action their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor.

Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding domain the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for transactivation used for communication with the translational apparatus.

Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol. In the absence of steroids, they associate in an aporeceptor complex containing chaperone or heatshock proteins (HSPs). The HSPs are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden. Receptor activity can be enhanced by phosphorylation of serine residues at their N-terminal as a result of another signal transduction pathway, a process called crosstalk.

Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from a precursor like retinol brought to the cell through the bloodstream or a completely intracellularly synthesised ligand like prostaglandin. These receptors are located in the nucleus and are not accompanied by HSPs. They repress their gene by binding to their specific DNA sequence when no ligand binds to them, and vice versa.

Certain intracellular receptors of the immune system are cytoplasmic receptors recently identified NOD-like receptors (NLRs) reside in the cytoplasm of some eukaryotic cells and interact with ligands using a leucine-rich repeat (LRR) motif similar to TLRs. Some of these molecules like NOD2 interact with RIP2 kinase that activates NF-κB signaling, whereas others like NALP3 interact with inflammatory caspases and initiate processing of particular cytokines like interleukin-1β. [45] [46]

First messengers are the signaling molecules (hormones, neurotransmitters, and paracrine/autocrine agents) that reach the cell from the extracellular fluid and bind to their specific receptors. Second messengers are the substances that enter the cytoplasm and act within the cell to trigger a response. In essence, second messengers serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction.

Calcium Edit

The release of calcium ions from the endoplasmic reticulum into the cytosol results in its binding to signaling proteins that are then activated it is then sequestered in the smooth endoplasmic reticulum [47] and the mitochondria. Two combined receptor/ion channel proteins control the transport of calcium: the InsP3-receptor that transports calcium upon interaction with inositol triphosphate on its cytosolic side and the ryanodine receptor named after the alkaloid ryanodine, similar to the InsP3 receptor but having a feedback mechanism that releases more calcium upon binding with it. The nature of calcium in the cytosol means that it is active for only a very short time, meaning its free state concentration is very low and is mostly bound to organelle molecules like calreticulin when inactive.

Calcium is used in many processes including muscle contraction, neurotransmitter release from nerve endings, and cell migration. The three main pathways that lead to its activation are GPCR pathways, RTK pathways, and gated ion channels it regulates proteins either directly or by binding to an enzyme.

Lipid messengers Edit

Lipophilic second messenger molecules are derived from lipids residing in cellular membranes enzymes stimulated by activated receptors activate the lipids by modifying them. Examples include diacylglycerol and ceramide, the former required for the activation of protein kinase C.

Nitric oxide Edit

Nitric oxide (NO) acts as a second messenger because it is a free radical that can diffuse through the plasma membrane and affect nearby cells. It is synthesised from arginine and oxygen by the NO synthase and works through activation of soluble guanylyl cyclase, which when activated produces another second messenger, cGMP. NO can also act through covalent modification of proteins or their metal co-factors some have a redox mechanism and are reversible. It is toxic in high concentrations and causes damage during stroke, but is the cause of many other functions like relaxation of blood vessels, apoptosis, and penile erections.

Redox signaling Edit

In addition to nitric oxide, other electronically activated species are also signal-transducing agents in a process called redox signaling. Examples include superoxide, hydrogen peroxide, carbon monoxide, and hydrogen sulfide. Redox signaling also includes active modulation of electronic flows in semiconductive biological macromolecules. [48]

Gene activations [49] and metabolism alterations [50] are examples of cellular responses to extracellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream [50] and the migration of neutrophils to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic program. [51]

Mammalian cells require stimulation for cell division and survival in the absence of growth factor, apoptosis ensues. Such requirements for extracellular stimulation are necessary for controlling cell behavior in unicellular and multicellular organisms signal transduction pathways are perceived to be so central to biological processes that a large number of diseases are attributed to their disregulation. Three basic signals determine cellular growth:

  • Stimulatory (growth factors)
    • Transcription dependent response
      For example, steroids act directly as transcription factor (gives slow response, as transcription factor must bind DNA, which needs to be transcribed. Produced mRNA needs to be translated, and the produced protein/peptide can undergo posttranslational modification (PTM))
    • Transcription independent response
      For example, epidermal growth factor (EGF) binds the epidermal growth factor receptor (EGFR), which causes dimerization and autophosphorylation of the EGFR, which in turn activates the intracellular signaling pathway . [52]

    The combination of these signals are integrated in an altered cytoplasmic machinery which leads to altered cell behaviour.

    Following are some major signaling pathways, demonstrating how ligands binding to their receptors can affect second messengers and eventually result in altered cellular responses.

      : A pathway that couples intracellular responses to the binding of growth factors to cell surface receptors. This pathway is very complex and includes many protein components. [53] In many cell types, activation of this pathway promotes cell division, and many forms of cancer are associated with aberrations in it. [54] : In humans, cAMP works by activating protein kinase A (PKA, cAMP-dependent protein kinase) (see picture), and, thus, further effects depend mainly on cAMP-dependent protein kinase, which vary based on the type of cell. : PLC cleaves the phospholipidphosphatidylinositol 4,5-bisphosphate (PIP2), yielding diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG remains bound to the membrane, and IP3 is released as a soluble structure into the cytosol. IP3 then diffuses through the cytosol to bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). These channels are specific to calcium and allow the passage of only calcium to move through. This causes the cytosolic concentration of Calcium to increase, causing a cascade of intracellular changes and activity. [55] In addition, calcium and DAG together works to activate PKC, which goes on to phosphorylate other molecules, leading to altered cellular activity. End-effects include taste, manic depression, tumor promotion, etc. [55]

    The earliest notion of signal transduction can be traced back to 1855, when Claude Bernard proposed that ductless glands such as the spleen, the thyroid and adrenal glands, were responsible for the release of "internal secretions" with physiological effects. [56] Bernard's "secretions" were later named "hormones" by Ernest Starling in 1905. [57] Together with William Bayliss, Starling had discovered secretin in 1902. [56] Although many other hormones, most notably insulin, were discovered in the following years, the mechanisms remained largely unknown.

    The discovery of nerve growth factor by Rita Levi-Montalcini in 1954, and epidermal growth factor by Stanley Cohen in 1962, led to more detailed insights into the molecular basis of cell signaling, in particular growth factors. [58] Their work, together with Earl Wilbur Sutherland's discovery of cyclic AMP in 1956, prompted the redefinition of endocrine signaling to include only signaling from glands, while the terms autocrine and paracrine began to be used. [59] Sutherland was awarded the 1971 Nobel Prize in Physiology or Medicine, while Levi-Montalcini and Cohen shared it in 1986.

    In 1970, Martin Rodbell examined the effects of glucagon on a rat's liver cell membrane receptor. He noted that guanosine triphosphate disassociated glucagon from this receptor and stimulated the G-protein, which strongly influenced the cell's metabolism. Thus, he deduced that the G-protein is a transducer that accepts glucagon molecules and affects the cell. [60] For this, he shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman. Thus, the characterization of RTKs and GPCRs led to the formulation of the concept of "signal transduction", a word first used in 1972. [61] Some early articles used the terms signal transmission and sensory transduction. [62] [63] In 2007, a total of 48,377 scientific papers—including 11,211 review papers—were published on the subject. The term first appeared in a paper's title in 1979. [64] [65] Widespread use of the term has been traced to a 1980 review article by Rodbell: [60] [66] Research papers focusing on signal transduction first appeared in large numbers in the late 1980s and early 1990s. [46]

    Signal transduction in Immunology Edit

    The purpose of this section is to briefly describe some developments in immunology in the 1960s and 1970s, relevant to the initial stages of transmembrane signal transduction, and how they impacted our understanding of immunology, and ultimately of other areas of cell biology.

    The relevant events begin with the sequencing of myeloma protein light chains, which are found in abundance in the urine of individuals with multiple myeloma. Biochemical experiments revealed that these so-called Bence Jones proteins consisted of 2 discrete domains –one that varied from one molecule to the next (the V domain) and one that did not (the Fc domain or the Fragment crystallizable region). [67] An analysis of multiple V region sequences by Wu and Kabat [68] identified locations within the V region that were hypervariable and which, they hypothesized, combined in the folded protein to form the antigen recognition site. Thus, within a relatively short time a plausible model was developed for the molecular basis of immunological specificity, and for mediation of biological function through the Fc domain. Crystallization of an IgG molecule soon followed [69] ) confirming the inferences based on sequencing, and providing an understanding of immunological specificity at the highest level of resolution.

    The biological significance of these developments was encapsulated in the theory of clonal selection [70] which holds that a B cell has on its surface immunoglobulin receptors whose antigen binding site is identical to that of antibodies that are secreted by the cell when it encounters antigen, and more specifically a particular B cell clone secretes antibodies with identical sequences. The final piece of the story, the Fluid mosaic model of the plasma membrane provided all the ingredients for a new model for the initiation of signal transduction viz, receptor dimerization.

    The first hints of this were obtained by Becker et al [71] who demonstrated that the extent to which human basophils—for which bivalent Immunoglobulin E (IgE) functions as a surface receptor – degranulate, depends on the concentration of anti IgE antibodies to which they are exposed, and results in a redistribution of surface molecules, which is absent when monovalent ligand is used. The latter observation was consistent with earlier findings by Fanger et al. [72] These observations tied a biological response to events and structural details of molecules on the cell surface. A preponderance of evidence soon developed that receptor dimerization initiates responses (reviewed in [73] ) in a variety of cell types, including B cells.

    Such observations led to a number of theoretical (mathematical) developments. The first of these was a simple model proposed by Bell [74] which resolved an apparent paradox: clustering forms stable networks i.e. binding is essentially irreversible, whereas the affinities of antibodies secreted by B cells increases as the immune response progresses. A theory of the dynamics of cell surface clustering on lymphocyte membranes was developed by DeLisi and Perelson [75] who found the size distribution of clusters as a function of time, and its dependence on the affinity and valence of the ligand. Subsequent theories for basophils and mast cells were developed by Goldstein and Sobotka and their collaborators, [76] [77] all aimed at analysis of dose response patterns of immune cells and their biological correlates. [78] For a recent review of clustering in immunological systems see. [79]

    Ligand binding to cell surface receptors is also critical to motility, a phenomenon that is best understood in single-celled organisms. An example is the detection and response to concentration gradients by bacteria [80] -–the classic mathematical theory appearing in. [81] A recent account can be found in [82]


    Part II: Knowledge Overview &mdash

    How bacteria talk to one another

    The Basics of Quorum Sensing

    Here are the general rules for quorum-sensing systems:

    1) Bacteria produce and release small molecules, called autoinducers, into the extracellular environment: At low cell density, when only a few bacterial cells are present, only a small amount of autoinducer can be made and it diffuses away. Because the autoinducer concentration is low, the bacteria cannot detect it. Under this condition, the bacteria act as individuals. As the cells divide and increase in number, they produce and release more autoinducer molecules into the environment the extracellular concentration of autoinducer increases in step with increasing cell-population-density. This principle is illustrated in Figure 11 in the context of bioluminescence.

    Figure 11: Quorum-Sensing Control of Bioluminescence.

    2) Typically, autoinducers are freely diffusible across the cell membrane, so the extracellular concentration is equal to the intracellular concentration. When the extracellular autoinducer reaches a critical threshold concentration, which is indicative of a particular cell population density, the bacteria detect the accumulated autoinducer using receptors (either in the cytoplasm or in the plasma membrane). In response, autoinducer-bound receptors regulate genes that underlie collective behaviors. Regulation involves the precise control of transcription factors that interact with RNA polymerase and this determines whether a gene will be transcribed or not. The types of genes being turned “on” or “off” by quorum sensing give the bacteria distinct behaviors or phenotypes in the low cell density and high cell density situations ( Figure 12 ). For example, quorum-sensing systems can control genes enabling biofilm formation, virulence factor production, antibiotic production, symbiosis , DNA uptake, etc. Typically, using quorum sensing, a given bacterial species will control between 200 and 600 genes (out of

    2,000–4,000 total genes) which are encoded at many locations in the bacterial genome, so a large proportion of a bacterium’s genome can be devoted to group behaviors ( Figure 12 ).

    Figure 12 A General Model for Transcription of Quorum-Sensing-Controlled Genes. Hundreds of genes may be turned on or off by quorum-sensing signaling pathways.

    Quorum Sensing Involves Signaling Pathways

    Accumulated autoinducers are detected in one of two ways:

    1) by cytoplasmic receptors or

    2) by plasma-membrane-bound receptors

    It is noteworthy to mention here that many eukaryotic signal transduction systems (such as steroid hormones [cytoplasmic receptor] and insulin [membrane receptor]) work analogously to these two types of bacterial quorum-sensing signal transduction systems.

    Cytoplasmic Receptors as Transcription Factors

    The simplest quorum-sensing systems to understand are the ones like those discovered by Engebrecht and Silverman in V. fischeri. Accumulated, extracellular autoinducer diffuses inside of the cell and binds to the cytoplasmic receptor (called LuxR). The cytoplasmic receptor is a transcription factor, which means that it binds to a specific promoter DNA sequence. This system acts as a switch: the cytoplasmic receptor will only bind to the DNA when it is bound to its autoinducer ( Figure 13 ). Once the autoinducer-bound cytoplasmic receptor binds the DNA, it then recruits and activates RNA polymerase to also bind the DNA. RNA polymerase then starts transcribing messenger RNA (mRNA) encoding the nearby genes. The mRNA, in turn, instructs ribosomes to synthesize the proteins encoded by the genes (see Central Dogma ). In our example of bioluminescence, the expressed genes encode the light-producing luciferase enzyme and the LuxI enzyme that makes the autoinducer.

    Figure 13 How Cytoplasmic Receptors Control Gene Expression. Autoinducer binds to a cytoplasmic receptor and induces a conformational change (causes a change in the shape of the protein). The receptor becomes able to bind DNA, recruit RNA polymerase, and allow the transcription of the nearby genes.

    Membrane-Spanning Receptors and Phosphorylation Cascades

    Many quorum-sensing systems involve plasma-membrane-bound receptor proteins. The domain of the receptor that is located on the outside of the cell possesses a pocket that binds a specific autoinducer. The domain of the receptor protein that resides on the inside of the cell is an enzyme with two activities called kinase and phosphatase.

    Kinases ( Figure 14 ) are enzymes that, using ATP as a chemical substrate, covalently link a phosphate to a particular amino acid on a protein. The addition of the phosphate to the protein serves a regulatory function it changes the activity of the protein.

    Figure 14 Protein Kinases. These enzymes covalently attach a phosphate, from adenosine triphosphate (ATP) to an amino acid of a protein.

    Phosphatases ( Figure 15 ) are enzymes that remove phosphate from a protein. Thus, kinases and phosphatases have opposing enzymatic activities.

    Figure 15 Protein Phosphatases. These enzymes remove a covalently bound phosphate from an amino acid of a protein.

    In the case of quorum sensing, at low cell density, when the autoinducer has not accumulated, its partner plasma-membrane-bound receptor acts as a kinase and phosphorylates itself ( Figure 16 ). That phosphate group is shuttled through a series of other intermediary proteins, ending with the transfer of the phosphate to a transcription factor . That phosphorylated transcription factor, together with RNA polymerase, causes genes that are needed for the bacteria to act as individuals to be transcribed while genes needed for group behaviors are not transcribed ( Figure 16 ).

    Figure 16 How Autoinducers Work through Plasma-Membrane-Spanning Receptors. These receptors are proteins that have an extracellular binding site and intracellular enzyme activities (a kinase and a phosphatase). Without autoinducer, the kinase portion of the receptor is active and it phosphorylates itself (that is, it puts a phosphate group on the receptor). That phosphate group is transferred through several intermediary proteins to a transcription factor that, with RNA polymerase, controls gene expression. Under this condition, genes for individual behaviors are turned on and genes for group behaviors are turned off. When an autoinducer binds to the partner plasma-membrane-bound receptor, it induces a conformational change in the receptor protein that turns the kinase part of the receptor off and turns the phosphatase part of the receptor on. The phosphatase removes phosphate from the receptor, reversing the flow through the intermediary proteins. In this scenario, genes for group behaviors are turned on and genes for individual behaviors are turned off.

    What happens at high cell density? The autoinducer levels increase, enabling autoinducer molecules to bind to the plasma-membrane-bound receptor. Autoinducer binding changes the receptor from being a kinase to being a phosphatase. The receptor removes the phosphate group from itself. This reverses the flow of phosphate from the transcription factor, through the intermediate proteins, to the receptor and ultimately these backward-flowing phosphates are removed from the receptor. Under this condition, genes required for individual behaviors are not transcribed while genes required for group behaviors are transcribed into mRNA and then made into proteins. ( Figure 16 ).

    The role of the positive-feedback loop

    Quorum-sensing systems also illustrate a prevalent control system in biology called “feedback loops.” If you study how cells make decisions, you will encounter feedback loops over and over again. Feedback loops are not unique to biology. Electrical engineers use feedback frequently in circuit design. A concise definition of positive feedback can be found in Wikipedia: “Positive feedback is a process that occurs in a feedback loop in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A.”

    Let us see how this principle plays out in quorum sensing. In Figure 17 , the input is the autoinducer, which triggers “activity A,” transcription of genes. Gene transcription generates a desired output, such as bioluminescence. However, it also generates more of the autoinducer production enzyme, which acts as “activity “B.” The enzyme activity then results in more input (the autoinducer), which results in more transcription (“activity A”).

    Figure 17 : A Positive Feedback Loop Drives Quorum Sensing. Autoinducer activates the transcription of the gene encoding the autoinducer-producing enzyme, along with the luciferase genes that produce bioluminescence. More autoinducer-producing enzymes are made and they produce more autoinducers (which causes more autoinducer-producing enzymes to be made, etc.). This is a positive feedback loop.

    What does positive feedback do? In this case, it causes a switch-like change in the behavior of the bacterial population. Once a certain level of autoinducer is reached (due to bacterial cell growth), the production of autoinducer suddenly increases rapidly because more of the autoinducer production enzyme is made. This “bolus-dose” of autoinducer encourages all of the nearby cells to switch into quorum-sensing mode presumably promoting commitment to and synchrony in the execution of group behaviors. Without positive feedback on autoinducer production, you can imagine that, overall, cells would experience only slowly increasing autoinducer concentrations making the transition sluggish. Such a communication system would be noisy and inefficient, with some cells detecting enough autoinducer to engage in quorum sensing while others that encounter less autoinducer, lagging behind in the quorum-sensing transition. It is this positive feedback loop in which the production of the communication molecule is activated by the quorum-sensing relay that led to the name “autoinducer.”

    Intra-species, Intra-genera, and Inter-species Communication

    Bacteria often use multiple autoinducers for quorum sensing and the chemical nature of each autoinducer encodes different information about “who” is in the vicinity. Take V. harveyi: it uses three different autoinducer chemicals for intra-species, intra-genera, and inter-species communication, respectively ( Figures 10 and 18 ). Only V. harveyi and its closest relative produce the chemical AI-1, suggesting that the AI-1 autoinducer is used for intraspecies communication. AI-1 is a homoserine lactone, similar to the homoserine lactone identified originally as the V. fischeri autoinducer. This is a common theme in quorum sensing: distinct homoserine lactone compounds, i.e., molecules that are similar but not identical, are used by different bacteria for intraspecies communication. Vibrios (all bacteria of the genus Vibrio) make another chemical called CAI-1, suggesting that CAI-1 is used for intra-genus communication. By contrast, the autoinducer chemical called AI-2 is broadly made among bacteria, so AI-2 is proposed to function in interspecies communication. V. harveyi has the ability to determine the ratio of AI-1:CAI-1:AI-2.

    Figure 18 Autoinducers Encode Information about Bacterial Identities. Only the V. harveyi species produces the chemical AI-1, suggesting that it is used for “private” communication with its closest relatives. CAI-1 is secreted and detected by all bacteria of the genus Vibrio, so is used for broader communication between different species of Vibrios. AI-2 is an autoinducer that is made by many diverse species of bacteria, so it is used for very broad interspecies communication.

    Interestingly, V. harveyi tailors its quorum-sensing-controlled behaviors based on which autoinducer signal dominates. Presumably, V. harveyi decodes the information in the relative concentrations of the three autoinducers to determine whether it and its relatives or, alternatively, some other bacterial species is in the majority of a mixed-species community. On the basis of that information, V. harveyi carries out quorum-sensing behaviors that are appropriate to its circumstances. This means that, through quorum sensing, bacteria can tell self from non-self!

    Who is making all these different autoinducers? In the above explanations concerning discoveries of components involved in quorum sensing, the bacteria under study were grown as single species in flasks in laboratories. This initial strategy was sensible for doing simple experiments to discover the basic principles of quorum sensing. However, in nature, bacteria live in complex and changing environments, in biofilms, and frequently, they live in communities with other bacterial species present.

    Take for example the human microbiome, which I mentioned earlier in this Narrative. Your mouth, for example, is a thriving community of many bacteria that live in biofilms on your teeth and gums. There are also very complex bacterial communities in the human gut, estimated at 1014 bacterial cells (more than the number of human cells in your body!) made up of 600 different species, primarily growing in biofilms. You can imagine that many autoinducers are present, that their levels vary (there is periodic fluid flow in the gut that could concentrate or wash away autoinducers) and changes in nutrients (depending on when and what a person eats) can allow particular bacteria to grow faster or slower at different times. Somehow, the individual bacteria in these diverse consortia have to be able to measure and interpret autoinducer information to discern how many and who their neighbors are so they can behave appropriately. Moreover, they have to be able to update their assessments to deal with changes in community composition.

    Scientists do not yet understand much about how quorum sensing works in the human microbiome (or any complicated mixed-species bacterial community) because it is early days in such studies. Here we, nonetheless, try to give insight into some possibilities based on what we do know from the findings discussed above. Figure 19 provides a picture of how we can begin to think about quorum sensing in communities containing multiple species of bacteria. For simplicity, we only consider intraspecies and interspecies autoinducers. The top panel of Figure 19 shows the mixed-species community. Imagine many different species of bacteria residing in close proximity to one another. In the Figure, each color pattern represents one bacterial species.

    Figure 19 A Model for How Quorum Sensing Works in Mixed-Species Communities. The lower left panel highlights the “yellow” species, which are numerous in the community. They encounter a high level of their own intra-species autoinducer (yellow triangles) as well as a high concentration of the inter-species autoinducer (blue triangles). That blend of autoinducers tells the “yellow” species that they are at high cell density but they have neighbors that are non-kin (in the top panel). On the other hand, the orange species of bacteria are low in number (top panel). The lower right panel highlights the “orange species” situation. The comparison of its own autoinducer (orange triangles) with that of the interspecies autoinducer (blue triangles) informs this bacterial species that it is far outnumbered by non-kin.

    Explorer’s Question: What information do you think the “yellow bacteria” in our cartoon can glean about their environment?

    Answer: The lower left panel highlights the “yellow” species. In our scheme, there are many “yellow” bacteria in the community. They encounter a high level of their own intra-species autoinducer (yellow triangles) as well as a high concentration of the inter-species autoinducer (blue triangles). That blend of autoinducer tells the “yellow” species that they are at high cell density but they have neighbors that are non-kin.

    Explorer’s Question: Take the “orange” species in the bottom right panel. What information do you think that lone orange bacterium infers from the autoinducer blend?

    Answer: In our cartoon, there are only a few bacteria of the “orange” species present (look at the original, top panel). The “orange” bacterial species detects none or only a very low level of its species-specific autoinducer (orange triangles) but it encounters a high level of the interspecies autoinducer (blue triangles). That combination of autoinducers tells the “orange” species that it and its kin are far outnumbered by non-kin.

    Going back to the top panel, in our scenario, the “yellow” species would likely turn on many quorum-sensing-controlled genes that help it prosper as a group. However, the “yellow” species might not turn on its entire repertoire of quorum-sensing-controlled genes because it would have detected that there also are many non-kin neighbors around that could compete for and take advantage of released molecules. The “yellow” species knows there are non-kin present due to the detection of the inter-species autoinducer. It might activate defensive behaviors to ensure it maintains the majority in the community.

    The “orange” species would not launch its quorum-sensing program because there are not enough members of its kin to productively act as a group. The “orange” species would likely wait and keep monitoring the situation until such time that it detects a higher level of its species-specific autoinducer (orange triangles). Such a change in the ratio of the different autoinducer molecules could alert the “orange” species that it was gaining in cell numbers in the mixed-species community.


    Seeing the Light: News in Neurospora Blue Light Signal Transduction

    H. Linden , . G. Macino , in Advances in Genetics , 1999

    IV MUTATIONAL ANALYSIS OF BLUE LIGHT SIGNAL TRANSDUCTION IN Neurospora

    During the past decades, a considerable effort has been made in the genetic dissection of the Neurospora blue light transduction pathway. Numerous mutants that seem to affect or participate in blue light signaling have been isolated (for review, see Linden et al., 1997a ). The most important and best examined Neurospora mutants in blue light signal transduction isolated to date are the white collar mutants ( Perkins et al., 1982 Harding and Shropshire, 1980 ). The white collar mutants have pigmented conidia, whereas the mycelia are white due to a specific deficiency in light-induced carotenoid biosynthesis. This is in contrast to the albino mutants, which reveal white mycelia and white conidia due to mutations in structural genes of carotene biosynthesis. The wc-1 and wc-2 mutants have been shown to be completely “blind” for almost all Neurospora blue light responses, and most of the blue-light-regulated genes cloned were reported to be not inducible by blue light in either a wc-1 or wc-2 mutant background. Most of the mutants reported previously, including several wc mutant alleles, were isolated either by chance or by visual screening without the application of a selection system ( Degli-Innocenti and Russo, 1984b ).

    In order to isolate new regulatory mutants that affect blue light perception in N. crassa and to carry out a saturating genetic dissection of “blind” mutants, a selection system has been developed ( Carattoli et al., 1995 ). Taking advantage of the fact that blindness does not seem to be lethal in Neurospora, all nonredundant blue light signal transduction components could be identified with this selection system. The light-induced al-3 promoter was fused to the coding region of the mtr gene, the product of which is responsible for the uptake of neutral aliphatic and aromatic amino acids in Neurospora ( Stuart et al., 1988 ). After transformation of a mtr – /trp – strain with this construct, the resulting strain (13-1) became light dependent for the uptake of tryptophan and of a toxic analogue of phenylalanine, p-fluorophenylalanine ( Linden et al., 1997c ). Strain 13-1 was able to grow on a medium supplemented with p-fluorophenylalanine in darkness only, as the al-3::mtr gene construct is not expressed under these conditions. In contrast, in the light the al-3::mtr promoter is induced, causing mtr expression and the uptake of the drug, which inhibits cell growth. Therefore, only mutants impaired in blue light perception or signal transduction will grow in the light in the presence of p-fluorophenylalanine. This selection system was successfully applied to the isolation of mutants that showed a decreased sensitivity for blue-light-regulated processes ( Carattoli et al., 1995 ). The blue-light-regulator mutants blr-1 and blr-2 revealed a pale-orange phenotype indicating decreased light induction of mycelial carotenoid biosynthesis. Furthermore, the mutants had decreased steady-state levels of mRNA for all light-regulated genes examined. In sexual crossing experiments, the mutations blr-1 and bk-2 fell into different segregation groups from wc-1 and wc-2. Consequently, they do not represent leaky alleles of the wc loci. In addition, the selection system was used for the isolation of wc mutants after ultraviolet mutagenesis ( Linden et al., 1997c ). In spite of an exhaustive screening, no additonal wc loci other than wc-1 and wc-2 were isolated. Therefore, the wc-1 and wc-2 genes seem to be the only nonredundant loci present in Neurospora that lead to a complete “blindness” toward light.

    The selection system just described has a further application: The selection strain 13-1 is unable to take up aromatic amino acids in the dark. After ultraviolet mutagenesis, growth of 13-1 on tryptophan in darkness resulted in the isolation of mutants ccb-1 and ccb-2 (for constitutive carotenoid biosynthesis), which showed a light-grown phenotype even in the dark ( Linden et al., 1997c ). In spite of constitutive mycelial carotenoid biosynthesis in darkness, the mutants did not show increased mRNA levels of light-regulated genes in the dark. However, an increased expression of some light-regulated genes in comparison to the wild type occurred after light induction, indicating a function in blue light signaling at least for ccb-1. Its recessive nature together with the specific effects on light induction of carotenoid biosynthesis suggested a role for the ccb-1 gene product as transcriptional repressor of some light-regulated genes. The identification of dark repression sites in promoters of light-regulated genes pointed to the presence of such repressors in Neurospora ( Kaldenhoff and Russo, 1993 ). On the other hand, the ccb-2 gene product was proposed to act during the developmental process of conidiation.


    Visual Connection Questions

    Figure 20.12 Which of the following statements about the nitrogen cycle is false?

    1. Ammonification converts organic nitrogenous matter from living organisms into ammonium (NH4 + ).
    2. Denitrification by bacteria converts nitrates (NO3 - ) to nitrogen gas (N2).
    3. Nitrification by bacteria converts nitrates (NO3 - ) to nitrites (NO2 - ).
    4. Nitrogen fixing bacteria convert nitrogen gas (N2) into organic compounds.

    Figure 20.28 In which of the following regions would you expect to find photosynthetic organisms?

    1. The aphotic zone, the neritic zone, the oceanic zone, and the benthic realm.
    2. The photic zone, the intertidal zone, the neritic zone, and the oceanic zone.
    3. The photic zone, the abyssal zone, the neritic zone, and the oceanic zone.
    4. The pelagic realm, the aphotic zone, the neritic zone, and the oceanic zone.

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      Molecular Biology of Vision

      Theodore G. Wensel , Theodore G. Wensel , in Basic Neurochemistry (Eighth Edition) , 2012

      Phototransduction consists of a highly amplified cascade of light-triggered changes in protein conformation, and changes in interactions of proteins with one another and with guanine nucleotides

      Phototransduction is the generation of an electrochemical signal in response to absorbance of light ( Baylor, 1996 Burns & Arshavsky, 2005 Gross & Burns, 2011 Stryer, 1986 ). Photoreceptors are relatively depolarized in the dark, due to Na + ions entering the outer segment through light-sensitive channels, and as a result they continuously release the neurotransmitter glutamate. Light induces a biochemical cascade that causes a graded hyperpolarization through closing of the channels, with a resultant graded slowing of glutamate release.

      Whereas most excitable cells are in a hyperpolarized state in the absence of stimulation, with a membrane potential of somewhere between −90 mV (inside more negative than outside) and −60 mV, photoreceptors in the dark have membrane potentials close to −40 mV, so they are considered relatively depolarized. The molecules promoting hyperpolarization are Na,K-ATPase, which uses the energy derived from hydrolysis of ATP to pump Na + out of the cell and K + into the cytoplasm, and potassium-selective channels in the inner segment, which allow K + ions to diffuse out to a lower concentration in the extracellular space, thereby generating a deficit of positive charge inside the cell and a negative membrane potential. Balancing this outward positive current in the inner segment (where the K + channels are located) is the large inward current carried by Na + in the outer segment (see Chs. 3, 4 for further discussion).

      The channel catalyzing this inward current is a cyclic nucleotide-gated channel selective for cGMP. This channel is relatively nonspecific for physiological cations, but primarily conducts Na + ions from the extracellular space to the cytoplasm, due to the high extracellular Na + concentration. There is a complete circuit consisting of the extrusion of Na + ions and the outward diffusion of K + ions from the inner segment, and the diffusion primarily of Na + ions (partly balanced by outward diffusion of K + ions, leading to a reversal potential much lower than that expected for Na + -selective channels ( Yau & Nakatani, 1984 ) into the outer segment, known as the circulating dark current ( Hagins & Yoshikami, 1970 ). There is also a minor, but physiologically very important, component of the dark current carried by Ca 2+ ions. Ca 2+ ions are extruded by an electrogenic Na + /K + /Ca 2+ exchanger ( Schnetkamp, 2004 ) and leak back into the cell through the CNG channel.

      Why are these currents so important for phototransduction? The essence of phototransduction is a molecular mechanism whereby light impinging on the photoreceptor cells can be detected and communicated to the downstream neurons, the ON and OFF bipolar cells, and horizontal cells. Photoreceptors communicate with these downstream cells through their release of the excitatory neurotransmitter glutamate, and the release of glutamate is controlled by membrane potential through the action of voltage-gated Ca + channels, whose opening floods the presynaptic space with Ca 2+ , triggering synaptic vesicle fusion and glutamate release ( Heidelberger et al., 2005 ). In both rods and cones, glutamate release occurs in a graded fashion, controlled by the membrane potential, and therefore, ultimately, by light-dependent changes in current passing through the CNG channel. The current through this channel controls the membrane potential, and that current is controlled by the cytoplasmic concentration of cGMP, which in turn is controlled by light.

      How does light control the cGMP concentration? The answer begins with photoactivation of rhodopsin. Rhodopsin is in many ways a prototypical G-protein–coupled receptor (GPCR). In the dark it has an inverse agonist (a compound whose binding lowers the ability of a GPCR to activate G proteins), 11-cis retinaldehyde, covalently coupled (as a Schiff’s base) to a lysine residue in its transmembrane domain ( Fig. 51-4 ). In this state, rhodopsin has essentially no ability to catalyze the exchange of GTP for GDP on the α subunit of the heterotrimeric G protein of vision, transducin (Gαt). Absorption of light induces photoisomerization of retinal from 11-cis to all-trans with an unusually high quantum yield of 0.65 ( Kim et al., 2001 ). The quantum efficiency of rhodopsin combined with the amplification of the G-protein cascade allows rods to respond to very low levels of light, at the level of individual photons. The cistrans isomerization induces a conformational change in rhodopsin ( Figs. 51-4, 51-5 ). All-trans-retinal is a potent agonist, and converts rhodopsin to the activated form, metarhodopsin II (MII), which in turn catalyzes the conversion of Gαtβγ-GDP to Gαt-GTP+Gβγ, at a rate of a few hundred per second ( Fig. 51-6 ).

      Figure 51-4 . Molecular transformations of retinoids in photoreceptors during the primary events of vision and the photoreceptor portion of the visual cycle.

      Rhodopsin is formed when the aldehyde moiety of 11-cis-retinal forms a protonated Schiff’s base with lysine 296 of the apo-receptor opsin. Its absorbance spectrum shifts dramatically to the red, from a maximum absorbance in the ultraviolet (380 nm) to the visible (500 nm). Absorption by rhodopsin leads to a photoisomerization from all-trans to 11-cis, forming bathorhodopsin. In a series of protein conformational changes and deprotonation and protonation steps, bathorhodopsin relaxes to the form responsible for activating the G protein, metarhodopsin II. Ultimately, metarhodopsin II decays to metarhodopsin III, from which all-trans-retinal is hydrolyzed, generating a transient pool of free all-trans-retinal and opsin. Free all-trans-retinal is converted to all-trans-retinol by the action of a class of enzymes known as retinol de-hydrogenases (RDH), which use NADPH as the reductant. The all-trans-retinol can diffuse through the cell membrane and make its way to retinal pigmented epithelium, where further transformations of the visual cycle take place (see Fig. 51-10 ), eventually regenerating 11-cis-retinal.

      Figure 51-5 . Conformational activation of rhodopsin.

      Ribbon diagram of structure of dark, inactive state of rhodopsin (cyan ribbons) with the covalently coupled chromophore, 11-cis retinaldehyde shown in space-filling mode (cyan) (pdb file 1U19, Okada et al., 2004 ) superimposed on the structure of an active conformation of opsin (orange ribbons pdb file 3DQB Scheerer et al., 2008 ) with a C-terminal peptide from the visual G protein Gat bound (orange space-filling model) at its cytoplasmic face. All molecular graphics in this chapter were rendered with UCSF Chimera

      Figure 51-6 . G protein activation by metarhodopsin II.

      In the dark, the visual G protein transducin exists primarily as a heterotrimer, Gαβγ, with GDP bound to the Gαt subunit. This is the inactive state of the G protein, and it interacts only weakly with rhodopsin. GDP dissociation is extremely slow, occurring with a time constant of 10,000s. Upon light activation and formation of metarhodopsin II (MII), the heterotrimer binds MII, which induces a conformational change that allows rapid GDP dissociation. In the absence of GTP, this complex of MII (shown here as a dimer of MII and rhodopsin), and nucleotide-free Gαβγ is very stable. Within the rod outer segment GTP concentration is on the order of 10−3 mol/L, so that GDP binds very rapidly to the nucleotide-free Gαt subunit. GTP binding induces a conformational change (see Fig. 51-7 ) that causes Gαt–GTP to dissociate both from Gαβγ and MII.

      Structures are based on the following pdb files: 1GOT ( Lambright et al., 1996 ) 3DQ ( Pettersen et al., 2004 ) and 1TND ( Noel et al., 1993 ).

      The significance of Gαt–GTP formation is that this complex controls the activity of a catalytically potent cGMP-specific phosphodiesterase, PDE6 ( Wensel, 1993 ). PDE6 is a heterotetrameric protein consisting of two large (nearly 100 kDa each) catalytic subunits, PDE6αβ, and two identical small inhibitory subunits, PDE6γ. The dark GDP-bound state of Gαt has very low affinity for PDE6, but GTP triggers a conformational change that dramatically enhances its ability to activate PDE6 ( Figs. 51-7, 51-8 ). When PDE6γ is bound to the catalytic subunits and Gαt-GTP is absent, then the activity of PDE6 is about one one-thousandth of its maximal activity. Gαt-GTP binds to this complex, and apparently pushes PDE6γ into a position that no longer blocks catalytic activity. In this state, with Gαt-GTP bound, PDE6 hydrolyzes cGMP with a catalytic efficiency on the order of 10 8 M −1 -s −1 , near the diffusion limit. As the cytoplasmic concentration of cGMP rapidly falls, cGMP dissociates from the CNG channel, channels close, the dark current is reduced or abolished, and the membrane potential becomes hyperpolarized. The dark current is reduced in a graded fashion over a wide range of light intensities, ranging from one-photon excitation of individual dark-adapted rods, to a rain of hundreds of thousands of photons per cell, required to approach saturation of light-adapted cones. The activation of PDE6 by Gαt-GTP is greatly enhanced by the lipid surface of the disk membrane ( Malinski & Wensel, 1992 Melia et al., 2000 ), to which both are tethered by covalently attached lipid groups, N-terminal fatty acyl modifications for Gαt, ( Kokame et al., 1992 Neubert et al., 1992 Z. Yang & Wensel, 1992b ), and both farnesyl and geranylgeranyl isoprenoids attached to the C-termini of PDE6αβ catalytic subunits ( Anant et al., 1992 Qin et al., 1992 ).

      Figure 51-7 . Conformational activation of transducin, Gαt.

      Ribbon diagram of structure of dark, inactive state of Gαt (cyan ribbons) with bound GDP shown in space-filling mode (cyan) (pdb file 1TAG, ( Lambright et al., 1994 ) superimposed on the structure of an active conformation of Gαt (orange ribbons pdb file 1TNDb ( Noel et al., 1993 ) with a non-hydrolyzable GTP analogue bound (orange space-filling model coordinated Mg 2+ in black).

      Figure 51-8 . Activation of PDE6 by activated transducin, Gαt-GTP.

      PDE6 is kept at a very low level of activity (PDE6i) in the dark by its inhibitory PDE6γ subunits. In its GTP-bound form, Gαt binds tightly to PDE6 and relieves the inhibitory constraint imposed by PDE6γ, forming the active form PDE6*, and allowing rapid catalysis of cGMP hydrolysis.

      Structures taken from pdb file 1FQJ, Slep et al., 2001 (Gαt and C-terminal fragment of PDE6γ), and from unpublished electron microscopy data, courtesy of Dr. Zhixian Zhang (PDE6).


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