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How does receptor downregulation/upregulation work?

How does receptor downregulation/upregulation work?


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My understanding is that if a cell is flooded with a certain neurotransmitter, it may decrease the density of that neurotransmitter. What I don't understand is how.

Is it a direct physical result of the receptor-ligand complex being internalized? I.e., the receptors simply aren't there anymore, because they've been internalized?

Or, does the internalization of specific receptor-ligand complexes actually get sensed by the cell somehow, causing it to produce fewer receptors in the future?


Both internalization (sometimes with degradation) and changes in gene expression can occur; the circumstances leading to the down regulation determine which (or both). It isn't necessary for receptors to be bound to their ligand to be internalized, though, and it isn't the internalization of receptors that causes changes in gene expression (I suppose it is possible that happens someplace, but not that I am familiar with). The processes involve activation of second messenger systems and kinases that either phosphorylate/dephosphorylate the receptors to mark them for internalization and/or degradation, or activate/deactivate transcription factors.

Here are two reviews with more information: one is newer but focused on a single class of receptors and fairly in-depth; the other is a bit dated but more broad, but brief:

Williams, J. T., Ingram, S. L., Henderson, G., Chavkin, C., von Zastrow, M., Schulz, S.,… & Christie, M. J. (2013). Regulation of µ-opioid receptors: Desensitization, phosphorylation, internalization, and tolerance. Pharmacological reviews, 65(1), 223-254.

Tsao, P., & von Zastrow, M. (2000). Downregulation of G protein-coupled receptors. Current opinion in neurobiology, 10(3), 365-369.

You can also read about long term depression, which is different from homeostatic responses to ligand concentrations, but it does seem to serve a homeostatic function to keep overall synaptic strengths from growing indefinitely, and the molecular pathways are very similar (and it is a very well-studied phenomenon so you will find a lot of accessible information).


Receptor downregulation and desensitization enhance the information processing ability of signalling receptors

In addition to initiating signaling events, the activation of cell surface receptors also triggers regulatory processes that restrict the duration of signaling. Acute attenuation of signaling can be accomplished either via ligand-induced internalization of receptors (endocytic downregulation) or via ligand-induced receptor desensitization. These phenomena have traditionally been viewed in the context of adaptation wherein the receptor system enters a refractory state in the presence of sustained ligand stimuli and thereby prevents the cell from over-responding to the ligand. Here we use the epidermal growth factor receptor (EGFR) and G-protein coupled receptors (GPCR) as model systems to respectively examine the effects of downregulation and desensitization on the ability of signaling receptors to decode time-varying ligand stimuli.

Results

Using a mathematical model, we show that downregulation and desensitization mechanisms can lead to tight and efficient input-output coupling thereby ensuring synchronous processing of ligand inputs. Frequency response analysis indicates that upstream elements of the EGFR and GPCR networks behave like low-pass filters with the system being able to faithfully transduce inputs below a critical frequency. Receptor downregulation and desensitization increase the filter bandwidth thereby enabling the receptor systems to decode inputs in a wider frequency range. Further, system-theoretic analysis reveals that the receptor systems are analogous to classical mechanical over-damped systems. This analogy enables us to metaphorically describe downregulation and desensitization as phenomena that make the systems more resilient in responding to ligand perturbations thereby improving the stability of the system resting state.

Conclusion

Our findings suggest that in addition to serving as mechanisms for adaptation, receptor downregulation and desensitization can play a critical role in temporal information processing. Furthermore, engineering metaphors such as the ones described here could prove to be invaluable in understanding the design principles of biological systems.


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Self-regulation of the autonomic nervous system (ANS) can essentially be broken down into two opposing functions: it goes up or it goes down!

In a car, we can press the gas pedal to access more energy, or the brake pedal to slow down or stop. Similarly, the ANS has two parts, or branches: the sympathetic nervous system (SNS), which makes us go up into greater arousal, and the parasympathetic nervous system (PNS), which helps us come down into calmer, less aroused states.

Upregulation means there’s more firing of nerve cells (neurons) along a nerve pathway. So, upregulation of the SNS refers to when this “going up” branch of the nervous system is more active. This “pressing of the gas pedal” increases the amount of energy available in the body. This is why the SNS is often referred to as the “fight-or-flight” nervous system, although it can also upregulate in pleasant situations requiring more energy.

Its opposite, and the focus of this article, is downregulation. Sympathetic downregulation brings down the charge along the pathways of the SNS. At the same time, the PNS upregulates, which helps the SNS downregulate. (We will examine the important exception to this general rule in a future article.)

Both upregulation and downregulation of the SNS are biological processes that we can feel and experience happening within us. Recently, a woman I work with in therapy was able to describe the involuntary muscular tensions, unpleasant pangs, and fluttering sensations of her anxiety (upregulation). She also described the wonderful (downregulation) sensations of her body finally letting go into blissful sleep when she settles down in bed at night.

As most of us can intuit, SNS upregulation can feel terrible when it’s a response to something stressful happening. However, SNS upregulation can also feel great when it’s in response to something fun or exciting: our team scoring a touchdown, or dancing when our favorite song comes on. In contrast, SNS downregulation almost always feels soothing, calming, or relaxing.

I am focusing on SNS downregulation because it’s incompatible with states of anxiety, rage, or stress. Additionally, SNS downregulation keeps the SNS in check, so that it doesn’t “overshoot” and produce too much stress to effectively cope with a problem.

So, then, how do we encourage SNS downregulation? How do we help the body settle down into a state in which it can rest, digest, and repair? For that matter, how do we know when we’re in a downregulated state?

Well, here’s the catch. Downregulating the stress response is an acquired capacity. It’s like a muscle: you have to build it over time in order for it to be strong.

Although infants are born with the capacity for stress response (fussing, crying, etc.), their parasympathetic pathways, which help downregulate the SNS stress response, are not online at birth. This means babies can go up, but they can’t come down on their own. (They will go into a “freeze” state if ignored long enough this looks calm, but it really isn’t.) The baby’s nervous system develops the ability to calm down through thousands and thousands of supportive, soothing interactions with caregivers. At first, the caregiver is essentially functioning as the child’s parasympathetic nervous system. The development of this “braking system” continues throughout childhood, through continued positive interactions that meet the child’s needs.

There are many situations in which a child may not receive enough soothing in order to learn to downregulate sufficiently. These situations are not always the fault of the parents. Perhaps the child’s mother had a lot of her own unmanaged anxiety, was depressed, and/or experienced posttraumatic stress. Or maybe the family lived in poverty, with constant stressors impacting everyone’s sense of safety. Perhaps someone in the family passed away or suffered a major illness, rendering them unavailable for care. Maybe the child grew up in wartime or, unbeknownst to their parents, was frequently bullied at school.

Great things happen when we are parasympathetically dominant. Our breath is full, slow, and deep. The digestive system works well. The body can focus on repair, including reduction of inflammation, tissue repair, and hormone production. Subjectively, people feel fully present and alive. Many report feeling a pleasant softness and warmth, perhaps even throughout their bodies.

It’s important to point out that disconnecting from stress is not the same as resolving (downregulating) it. Alcohol and drugs, eating disorders, exercise or sexual compulsion, or even “zoning out” on the internet may make the chronically stuck upregulation of the SNS seem to go away for a time. However, as the people I work with in the therapy room could tell you, it’s not the same as sinking into a lovely, full-body sense of calm and relaxation.

Great things happen when we are parasympathetically dominant. Our breath is full, slow, and deep. The digestive system works well. The body can focus on repair, including reduction of inflammation, tissue repair, and hormone production. Subjectively, people feel fully present and alive. Many report feeling a pleasant softness and warmth, perhaps even throughout their bodies. When the SNS is on “standby” and the PNS is more active, people have a “buffer” for stress. They have energy to get through their day, but they can stay calm and present in challenging situations.

One of my first tasks in therapy is to assess and support the person’s ability to downregulate their stress responses. After they are provoked by something, how quickly and smoothly does their system deactivate? Are they still bothered by a small aversive event hours or days afterward?

Here’s a vital point often overlooked by therapists who haven’t had sufficient training in this area: In therapy, it is essential to make sure the person has the ability to downregulate the stress response before going into highly stressful material. In other words, you should never go into material that’s overwhelming, because overwhelming inherently means it’s bigger than your capacity to deal with it. So instead of the issue resolving, more symptoms arise. The way around this is to first support the capacity for downregulation. Then, only after this “braking system” is on board, take the difficult material a small bit at a time.

If someone doesn’t have a strong enough ability to come out of the stress response, how can they develop it?

  • Therapy: Working with downregulation of the stress response can be tricky, as it involves the deepest survival energies of the body. It is advisable to work with a therapist who has extensive training in this area. Remember, SNS downregulation was originally designed to come online under the guidance of another person (usually a parent) whose nervous system is well-developed.
  • Relaxation: Some people benefit from seeking activities or situations that cause the relaxation response and then deliberately spending time “feeling into” the resulting good sensations in their body. However, in relaxation states, some people experience a rebound in tension, stress, or anxiety. This is called “relaxation-induced anxiety” (RIA) or, in severe cases, “relaxation-induced panic.” In my experience, people with RIA are well served by working with a trained practitioner.
  • Physical exercise: Exercise is often helpful, as it tends to burn off excess SNS charge and encourage the production of endorphins. Exercise promotes good mood, self-esteem, and a sense of accomplishment.
  • Meditation: There are many forms of meditation, some of which specifically aim to produce downregulated states. However, in my experience, meditation can be unhelpful for some people who have a lot of traumatic response stored in their nervous systems. In these cases, their nervous systems simply won’t cooperate, and those around them may not have the awareness or tools to work with this issue.
  • Resonance: Simply put, resonance is the feeling you get from being around another person or other living being. I usually explain it by asking people to think of how they feel when they place their open palm onto the rib cage of a calm, happy dog. That feeling of warmth, relaxation, and well-being is a downregulatory feeling obtained via resonance with the dog’s nervous system. Of course, when others around us are tense, our bodies tend to pick up on that and become tense too. Thus, being around stressed, anxious, or angry people is usually the opposite of what’s needed to develop SNS downregulation.

In summary, the ability to go within and really settle oneself is developed during infancy and childhood. This capacity to downregulate stress states is important in maintaining health, relationships, and happiness. Those whose life circumstances didn’t permit development of this capacity during childhood can still develop it through awareness and work with a skilled professional.


Coordinated regulation of CB1 cannabinoid receptors and anandamide metabolism stabilize network activity during homeostatic scaling down

Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the post-synaptic compartments that regulate synaptic transmission, plasticity, and neuronal excitability throughout much of the brain, by activating pre-synaptic cannabinoid receptor CB1. The eCB system is well situated to regulate neuronal network properties and coordinate pre- and post-synaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. We show that in mature cultured rat cortical neurons, chronic bicuculline treatment, known to induce homeostatic scaling-down, induces a coordinated adaptation to enhance tonic eCB signaling. Hyperexcitation triggers down regulation of fatty acid amide hydrolase (FAAH), the lipase that degrades the eCB anandamide. Subsequently, we measured an accumulation of anandamide and related metabolites, and an upregulation of total and cell surface CB1. We show that bicuculline induced downregulation of surface AMPA-type glutamate receptors and upregulation of CB1 occur through independent mechanisms. Finally, using live-cell microscopy of neurons expressing an extracellular fluorescent glutamate reporter (iGluSnFR), we confirm that cortical neurons in vitro exhibit highly synchronized network activity, reminiscent of cortical up-states in vivo. Up-state like activity in mature cortical cultures requires CB1 signaling under both control conditions and following chronic bicuculline treatment. We propose that during the adaptation to chronic neuronal hyperexcitation, tonic eCB signaling is enhanced through coordinated changes in anandamide metabolism and cell-surface CB1 expression to maintain synchronous network activity.

Significance statement Neurons are remarkably resilient to perturbations in network activities thanks to the expression of overlapping homeostatic adaptations. In response to network hyperactivity or silencing, neurons can respond through changes in excitatory and inhibitory post-synaptic neurotransmitter receptors, probability of pre-synaptic neurotransmitter release, or changes in membrane excitability. The endocannabinoid system is a prominent signaling pathway at many synapses that is known to be involved in multiple forms of short and long-term synaptic plasticity. Here we find that components of the endocannabinoid system are upregulated in response to chronic hyperexcitation of cultured cortical neurons, and that endocannabinoid signaling is required to maintain synchronized network activity. This work supports a novel tonic homeostatic function for the endocannabinoid system in neurons.


2.2. Regulators of upregulation

A number of factors regulate different features of nicotine-induced upregulation. These include differences in nAChR subunit composition, changes in temperature and the release of pro-inflammatory cytokines all of which further complicate interpretation of different studies.

2.2.1. nAChR subunit composition

Several studies have determined that nAChR subunit composition can alter different aspects of nicotine-induced upregulation. If 㬤 replaces 㬢 subunits in either 㬓- or 㬔-containing nAChRs, the upregulation as assayed by the fold-increase of radio-labeled agonist binding in transfected cells is highly reduced [118, 120, 121]. The findings are somewhat ambiguous because replacement of 㬢 subunits by 㬤 causes an increase in total radio-labeled agonist binding without nicotine treatment as if the 㬤-containing receptors are already upregulated without any nicotine treatment. There are also examples where addition of 㬤 to either 㬖 subunits [122] or 㬓 [123] subunits did result in significant degree of upregulation by nicotine.

The addition of two accessory subunits, 㬕 or 㬣 subunits to nAChRs appeared to block upregulation or downregulation by nicotine in several regions of the brain [124, 125]. 㬕 subunits were found almost exclusively associated with 㬔㬢 receptors in the several brain areas, and no nicotine-induced upregulation was observed [125]. A recent finding that 㬔㬢 receptors in dopaminergic neurons in the VTA are not upregulated by nicotine [57], raises the question whether 㬔㬢 receptors in these neurons are associated with 㬕. Since only a small percentage of receptors contain 㬕 subunits, the contribution from this upregulation-resistant receptor population may be too small to make an impact on a higher population of 㬔㬢 receptors that can be upregulated. It is also possible that the addition of 㬕 subunits to 㬔㬢 receptors has an effect similar to that observed with the addition of 㬤 subunits, where an increase in binding is observed without nicotine treatment as if the subunit addition causes upregulation without nicotine treatment. Interestingly, no nicotine-induced downregulation of 㬖 receptors in the striatum was observed if 㬣 subunits were present [124]. In mammalian cell lines co-expression of 㬣 subunits increased 㬖㬢 and 㬖㬤 receptor levels and the nicotine-induced upregulation of 㬖㬢㬣 receptors was enhanced compared to 㬖㬢 receptors [122]. These effects of 㬣 subunits may help explain why in the striatum 㬖-containing receptors without 㬣 are downregulated by nicotine, while those containing 㬣 are unaffected [124].

We have compared the nicotine-induced upregulation of 㬓㬢, 㬔㬢 and 㬖㬢 nAChRs in transfected cells [126]. Chronic nicotine exposure upregulated these receptors that showed differences in upregulation time course and concentration-dependence. The 㬖㬢 receptor upregulation required higher nicotine concentrations than for 㬔㬢 but lower than for 㬓㬢 receptors. The 㬖㬢 upregulation occurred 10-fold faster than for 㬔㬢 and slightly faster than for 㬓㬢. The data suggest that nicotinic receptor upregulation is subtype specific such that 㬖-containing receptors upregulate in response to transient, high nicotine exposures while sustained, low nicotine exposures upregulate 㬔㬢 receptors.

2.2.2. Temperature

Lowering the temperature reduces the turnover of subunits [127�], which in turn favors the assembly and folding of muscle nicotinic receptors [130]. For several nAChR subtypes transfected into mammalian cell lines, lowering the temperature to 29 or 30ଌ greatly increases the number of high-affinity agonist binding sites on the nAChRs [122, 131]. To some degree, these temperature-evoked increases correlate with an increase in subunit protein levels [126], but this question has not been carefully investigated. 㬔㬢 receptors appear to be an exception as a 12-fold increase in ligand binding was observed with no change in total subunit protein [131]. These effects of temperature may combine with the effects of nicotine since cigarette smoking causes a drop in skin temperature of 1.5 ଌ [132].

2.2.3. Cytokines

Pro Inflammatory cytokines such as TNF-α and IL-1 β can regulate nicotine-induced upregulation of nAChRs [121, 133]. These cytokine effects are likely important in regulating nAChRs on blood cells in the periphery but also for nAChRs in brain (see [134, 135], for a review). TNF-α release enhances the nicotine-induced upregulation of 㬔㬢 and 㬓㬢 receptors. This enhancement was attributed to an increase in receptor number as this enhancement was sensitive to transcriptional and translational inhibitors [121]. The response to pro inflammatory cytokines was dependent on subunit composition with differences that depended on β subunit subtype. 㬗-type nAChRs antagonize pro-inflammatory cytokine release [136] that may act to counter balance TNF-α enhancement of 㬔㬢 receptor upregulation. With the emerging concept of cholinergic modulation of inflammatory response, cross talk between inflammatory mediators and nicotinic receptors is becoming evident and should provide new insights for therapeutic interventions for inflammatory bowel diseases.


Plasma Membrane Hormone Receptors

Amino acid derived hormones and polypeptide hormones are not lipid-derived (lipid-soluble) and therefore cannot diffuse through the plasma membrane of cells. Lipid insoluble hormones bind to receptors on the outer surface of the plasma membrane, via plasma membrane hormone receptors . Unlike steroid hormones, lipid insoluble hormones do not directly affect the target cell because they cannot enter the cell and act directly on DNA. Binding of these hormones to a cell surface receptor results in activation of a signaling pathway this triggers intracellular activity and carries out the specific effects associated with the hormone. In this way, nothing passes through the cell membrane the hormone that binds at the surface remains at the surface of the cell while the intracellular product remains inside the cell. The hormone that initiates the signaling pathway is called a first messenger , which activates a second messenger in the cytoplasm, as illustrated in Figure (PageIndex<2>).

Figure (PageIndex<2>): The amino acid-derived hormones epinephrine and norepinephrine bind to beta-adrenergic receptors on the plasma membrane of cells. Hormone binding to receptor activates a G-protein, which in turn activates adenylyl cyclase, converting ATP to cAMP. cAMP is a second messenger that mediates a cell-specific response. An enzyme called phosphodiesterase breaks down cAMP, terminating the signal.

One very important second messenger is cyclic AMP (cAMP). When a hormone binds to its membrane receptor, a G-protein that is associated with the receptor is activated G-proteins are proteins separate from receptors that are found in the cell membrane. When a hormone is not bound to the receptor, the G-protein is inactive and is bound to guanosine diphosphate, or GDP. When a hormone binds to the receptor, the G-protein is activated by binding guanosine triphosphate, or GTP, in place of GDP. After binding, GTP is hydrolysed by the G-protein into GDP and becomes inactive.

The activated G-protein in turn activates a membrane-bound enzyme called adenylyl cyclase . Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP, in turn, activates a group of proteins called protein kinases, which transfer a phosphate group from ATP to a substrate molecule in a process called phosphorylation. The phosphorylation of a substrate molecule changes its structural orientation, thereby activating it. These activated molecules can then mediate changes in cellular processes.

The effect of a hormone is amplified as the signaling pathway progresses. The binding of a hormone at a single receptor causes the activation of many G-proteins, which activates adenylyl cyclase. Each molecule of adenylyl cyclase then triggers the formation of many molecules of cAMP. Further amplification occurs as protein kinases, once activated by cAMP, can catalyze many reactions. In this way, a small amount of hormone can trigger the formation of a large amount of cellular product. To stop hormone activity, cAMP is deactivated by the cytoplasmic enzyme phosphodiesterase , or PDE. PDE is always present in the cell and breaks down cAMP to control hormone activity, preventing overproduction of cellular products.

The specific response of a cell to a lipid insoluble hormone depends on the type of receptors that are present on the cell membrane and the substrate molecules present in the cell cytoplasm. Cellular responses to hormone binding of a receptor include altering membrane permeability and metabolic pathways, stimulating synthesis of proteins and enzymes, and activating hormone release.


Plasma Membrane Hormone Receptors

Amino acid derived hormones and polypeptide hormones are not lipid-derived (lipid-soluble) and therefore cannot diffuse through the plasma membrane of cells. Lipid insoluble hormones bind to receptors on the outer surface of the plasma membrane, via plasma membrane hormone receptors. Unlike steroid hormones, lipid insoluble hormones do not directly affect the target cell because they cannot enter the cell and act directly on DNA. Binding of these hormones to a cell surface receptor results in activation of a signaling pathway this triggers intracellular activity and carries out the specific effects associated with the hormone. In this way, nothing passes through the cell membrane the hormone that binds at the surface remains at the surface of the cell while the intracellular product remains inside the cell. The hormone that initiates the signaling pathway is called a first messenger, which activates a second messenger in the cytoplasm, as illustrated in Figure 2.

Figure 2. The amino acid-derived hormones epinephrine and norepinephrine bind to beta-adrenergic receptors on the plasma membrane of cells. Hormone binding to receptor activates a G-protein, which in turn activates adenylyl cyclase, converting ATP to cAMP. cAMP is a second messenger that mediates a cell-specific response. An enzyme called phosphodiesterase breaks down cAMP, terminating the signal.

One very important second messenger is cyclic AMP (cAMP). When a hormone binds to its membrane receptor, a G-protein that is associated with the receptor is activated G-proteins are proteins separate from receptors that are found in the cell membrane. When a hormone is not bound to the receptor, the G-protein is inactive and is bound to guanosine diphosphate, or GDP. When a hormone binds to the receptor, the G-protein is activated by binding guanosine triphosphate, or GTP, in place of GDP. After binding, GTP is hydrolysed by the G-protein into GDP and becomes inactive.

The activated G-protein in turn activates a membrane-bound enzyme called adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP, in turn, activates a group of proteins called protein kinases, which transfer a phosphate group from ATP to a substrate molecule in a process called phosphorylation. The phosphorylation of a substrate molecule changes its structural orientation, thereby activating it. These activated molecules can then mediate changes in cellular processes.

The effect of a hormone is amplified as the signaling pathway progresses. The binding of a hormone at a single receptor causes the activation of many G-proteins, which activates adenylyl cyclase. Each molecule of adenylyl cyclase then triggers the formation of many molecules of cAMP. Further amplification occurs as protein kinases, once activated by cAMP, can catalyze many reactions. In this way, a small amount of hormone can trigger the formation of a large amount of cellular product. To stop hormone activity, cAMP is deactivated by the cytoplasmic enzyme phosphodiesterase, or PDE. PDE is always present in the cell and breaks down cAMP to control hormone activity, preventing overproduction of cellular products.

The specific response of a cell to a lipid insoluble hormone depends on the type of receptors that are present on the cell membrane and the substrate molecules present in the cell cytoplasm. Cellular responses to hormone binding of a receptor include altering membrane permeability and metabolic pathways, stimulating synthesis of proteins and enzymes, and activating hormone release.


28.2 How Hormones Work

In this section, you will explore the following questions:

Connection for AP ® Courses

Much of the information in this section is an application of the material we explored in the Cell Communication chapter about cell communication and signaling pathways. Hormones are chemical signals (ligands) that mediate changes in target cells by binding to specific receptors. Even though hormones released by endocrine glands can travel long distances through the blood and come into contact with many different cell types, they only affect cells that possess the necessary receptors. Depending on the location of the receptor on the target cell and the chemical structure of the hormone, for example, whether or not it is lipid-soluble, hormones can mediate changes directly by binding to intracellular hormone receptors and modulating gene expression (transcription and translation), or indirectly by binding to cell surface receptors and simulating signaling pathways.

The hormone binds to its receptor like a key fits a lock. Because a lipid-derived hormone such as a steroid hormone can diffuse across the membrane of the target cell, they bind to intracellular receptors residing in the cytoplasm or in the nucleus. The cell signaling pathways induced by steroid hormones regulate specific genes by acting as transcription regulators. In turn, this affects the amount of protein produced. Lipid-derived hormones that are not steroids, for example, vitamin D and thyroxin, bind to receptors located in the nucleus of the target cell.

Because amino acid-derived hormones (with the exception of thyroxine) and polypeptide hormones are not lipid-soluble, they bind to plasma membrane hormone receptors located on the outer surface of the membrane. Unlike steroid hormones, they cannot act directly on DNA but activate a signaling pathway this triggers intracellular activity and carries out the specific effects associated with the hormone. The hormone that initiated the signaling pathway is called a first messenger. In the case of the epinephrine signaling pathway, binding of the amino acid-derived hormone epinephrine to its receptor activates a G-protein which, in turn, activates cAMP, a second messenger, ultimately resulting in a cellular response such as the conversion of glycogen to glucose.

Information presented and the examples highlighted in the section support concepts outlined in Big Idea 3 of the AP ® Biology Curriculum Framework. The AP ® Learning Objectives listed in the Curriculum Framework provide a transparent foundation for the AP ® Biology course, an inquiry-based laboratory experience, instructional activities, and AP ® exam questions. A learning objective merges required content with one or more of the seven science practices.

Big Idea 3 Living systems store, retrieve, transmit and respond to information essential to life processes.
Enduring Understanding 3.D Cells communicate by generating, transmitting and receiving chemical signals.
Essential Knowledge 3.D.3 Signal transduction pathways link signal reception with a cellular response.
Science Practice 1.5 The student can re-express key elements of natural phenomena across multiple representations in the domain.
Learning Objective 3.36 The student is able to describe a model that expresses the key elements of signal transduction pathways by which a signal is converted to a cellular response.

Hormones mediate changes in target cells by binding to specific hormone receptors. In this way, even though hormones circulate throughout the body and come into contact with many different cell types, they only affect cells that possess the necessary receptors. Receptors for a specific hormone may be found on many different cells or may be limited to a small number of specialized cells. For example, thyroid hormones act on many different tissue types, stimulating metabolic activity throughout the body. Cells can have many receptors for the same hormone but often also possess receptors for different types of hormones. The number of receptors that respond to a hormone determines the cell’s sensitivity to that hormone, and the resulting cellular response. Additionally, the number of receptors that respond to a hormone can change over time, resulting in increased or decreased cell sensitivity. In up-regulation, the number of receptors increases in response to rising hormone levels, making the cell more sensitive to the hormone and allowing for more cellular activity. When the number of receptors decreases in response to rising hormone levels, called down-regulation, cellular activity is reduced.

Receptor binding alters cellular activity and results in an increase or decrease in normal body processes. Depending on the location of the protein receptor on the target cell and the chemical structure of the hormone, hormones can mediate changes directly by binding to intracellular hormone receptors and modulating gene transcription, or indirectly by binding to cell surface receptors and stimulating signaling pathways.

Intracellular Hormone Receptors

Lipid-derived (soluble) hormones such as steroid hormones diffuse across the membranes of the endocrine cell. Once outside the cell, they bind to transport proteins that keep them soluble in the bloodstream. At the target cell, the hormones are released from the carrier protein and diffuse across the lipid bilayer of the plasma membrane of cells. The steroid hormones pass through the plasma membrane of a target cell and adhere to intracellular receptors residing in the cytoplasm or in the nucleus. The cell signaling pathways induced by the steroid hormones regulate specific genes on the cell's DNA. The hormones and receptor complex act as transcription regulators by increasing or decreasing the synthesis of mRNA molecules of specific genes. This, in turn, determines the amount of corresponding protein that is synthesized by altering gene expression. This protein can be used either to change the structure of the cell or to produce enzymes that catalyze chemical reactions. In this way, the steroid hormone regulates specific cell processes as illustrated in Figure 28.5.


37.2 How Hormones Work

By the end of this section, you will be able to do the following:

Hormones mediate changes in target cells by binding to specific hormone receptors . In this way, even though hormones circulate throughout the body and come into contact with many different cell types, they only affect cells that possess the necessary receptors. Receptors for a specific hormone may be found on many different cells or may be limited to a small number of specialized cells. For example, thyroid hormones act on many different tissue types, stimulating metabolic activity throughout the body. Cells can have many receptors for the same hormone but often also possess receptors for different types of hormones. The number of receptors that respond to a hormone determines the cell’s sensitivity to that hormone, and the resulting cellular response. Additionally, the number of receptors that respond to a hormone can change over time, resulting in increased or decreased cell sensitivity. In up-regulation , the number of receptors increases in response to rising hormone levels, making the cell more sensitive to the hormone and allowing for more cellular activity. When the number of receptors decreases in response to rising hormone levels, called down-regulation , cellular activity is reduced.

Receptor binding alters cellular activity and results in an increase or decrease in normal body processes. Depending on the location of the protein receptor on the target cell and the chemical structure of the hormone, hormones can mediate changes directly by binding to intracellular hormone receptors and modulating gene transcription, or indirectly by binding to cell surface receptors and stimulating signaling pathways.

Intracellular Hormone Receptors

Lipid-derived (soluble) hormones such as steroid hormones diffuse across the membranes of the endocrine cell. Once outside the cell, they bind to transport proteins that keep them soluble in the bloodstream. At the target cell, the hormones are released from the carrier protein and diffuse across the lipid bilayer of the plasma membrane of cells. The steroid hormones pass through the plasma membrane of a target cell and adhere to intracellular receptors residing in the cytoplasm or in the nucleus. The cell signaling pathways induced by the steroid hormones regulate specific genes on the cell's DNA. The hormones and receptor complex act as transcription regulators by increasing or decreasing the synthesis of mRNA molecules of specific genes. This, in turn, determines the amount of corresponding protein that is synthesized by altering gene expression. This protein can be used either to change the structure of the cell or to produce enzymes that catalyze chemical reactions. In this way, the steroid hormone regulates specific cell processes as illustrated in Figure 37.5.

Visual Connection

Heat shock proteins (HSP) are so named because they help refold misfolded proteins. In response to increased temperature (a “heat shock”), heat shock proteins are activated by release from the NR/HSP complex. At the same time, transcription of HSP genes is activated. Why do you think the cell responds to a heat shock by increasing the activity of proteins that help refold misfolded proteins?

Other lipid-soluble hormones that are not steroid hormones, such as vitamin D and thyroxine, have receptors located in the nucleus. While thyroxine is mostly hydrophobic, its passage across the membrane is dependent on transporter protein. Vitamin D diffuses across both the plasma membrane and the nuclear envelope. Once in the cell, both hormones bind to receptors in the nucleus. The hormone-receptor complex stimulates transcription of specific genes.

Plasma Membrane Hormone Receptors

Amino acid-derived hormones (with the exception of thyroxine) and polypeptide hormones are not lipid-derived (lipid-soluble) and therefore cannot diffuse through the plasma membrane of cells. Lipid insoluble hormones bind to receptors on the outer surface of the plasma membrane, via plasma membrane hormone receptors . Unlike steroid hormones, lipid insoluble hormones do not directly affect the target cell because they cannot enter the cell and act directly on DNA. Binding of these hormones to a cell surface receptor results in activation of a signaling pathway this triggers intracellular activity and carries out the specific effects associated with the hormone. In this way, nothing passes through the cell membrane the hormone that binds at the surface remains at the surface of the cell while the intracellular product remains inside the cell. The hormone that initiates the signaling pathway is called a first messenger , which activates a second messenger in the cytoplasm, as illustrated in Figure 37.6.

One very important second messenger is cyclic AMP (cAMP). When a hormone binds to its membrane receptor, a G-protein that is associated with the receptor is activated G-proteins are proteins separate from receptors that are found in the cell membrane. When a hormone is not bound to the receptor, the G-protein is inactive and is bound to guanosine diphosphate, or GDP. When a hormone binds to the receptor, the G-protein is activated by binding guanosine triphosphate, or GTP, in place of GDP. After binding, GTP is hydrolysed by the G-protein into GDP and becomes inactive.

The activated G-protein in turn activates a membrane-bound enzyme called adenylyl cyclase . Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP, in turn, activates a group of proteins called protein kinases, which transfer a phosphate group from ATP to a substrate molecule in a process called phosphorylation. The phosphorylation of a substrate molecule changes its structural orientation, thereby activating it. These activated molecules can then mediate changes in cellular processes.

The effect of a hormone is amplified as the signaling pathway progresses. The binding of a hormone at a single receptor causes the activation of many G-proteins, which activates adenylyl cyclase. Each molecule of adenylyl cyclase then triggers the formation of many molecules of cAMP. Further amplification occurs as protein kinases, once activated by cAMP, can catalyze many reactions. In this way, a small amount of hormone can trigger the formation of a large amount of cellular product. To stop hormone activity, cAMP is deactivated by the cytoplasmic enzyme phosphodiesterase , or PDE. PDE is always present in the cell and breaks down cAMP to control hormone activity, preventing overproduction of cellular products.

The specific response of a cell to a lipid insoluble hormone depends on the type of receptors that are present on the cell membrane and the substrate molecules present in the cell cytoplasm. Cellular responses to hormone binding of a receptor include altering membrane permeability and metabolic pathways, stimulating synthesis of proteins and enzymes, and activating hormone release.


SUMMARY

Opioid dependence and addiction are most appropriately understood as chronic medical disorders, like hypertension, schizophrenia, and diabetes. As with those other diseases, a cure for drug addiction is unlikely, and frequent recurrences can be expected but long-term treatment can limit the disease’s adverse effects and improve the patient’s day-to-day functioning.

The mesolimbic reward system appears to be central to the development of the direct clinical consequences of chronic opioid abuse, including tolerance, dependence, and addiction. Other brain areas and neurochemicals, including cortisol, also are relevant to dependence and relapse. Pharmacological interventions for opioid addiction are highly effective however, given the complex biological, psychological, and social aspects of the disease, they must be accompanied by appropriate psychosocial treatments. Clinician awareness of the neurobiological basis of opioid dependence, and information-sharing with patients, can provide insight into patient behaviors and problems and clarify the rationale for treatment methods and goals.


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