Receptors

Receptors

Receptors are typically glycoproteins located in cell membranes that specifically recognize and bind to ligands. These are smaller molecules (including drugs) that are capable of 'ligating' themselves to the receptor protein. This binding initiates a conformational change in the receptor protein leading to a series of biochemical reactions inside the cell (‘signal transduction’), often involving the generation of ‘secondary messengers’ that is eventually translated into a biological response (e.g. muscle contraction, hormone secretion). Although the ligands of interest to prescribers are exogenous compounds (i.e. drugs), receptors in human tissues have evolved to bind endogenous ligands such as neurotransmitters, hormones, and growth factors. Formation of the drug-receptor complex is usually reversible and the proportion of receptors occupied (and thus the response) is directly related to the concentration of the drug. Reversibility enables biological responses to be modulated and means that similar ligands may compete for access to the receptor. The term 'receptor' is usually restricted to describing proteins whose only function is to bind a ligand, but it is sometimes used more widely in pharmacology to include other kinds of drug target such as voltage-sensitive ion channels, enzymes and transporter proteins.

Introduction to receptor pharmacology

Receptor pharmacology is the study of the interactions of receptors with endogenous ligands, drugs/pharmaceuticals and other xenobiotics. In order to understand the molecular mechanism underlying a ligand's effect on physiological or therapeutic cellular responses a number of basic principles of receptor theory must be considered. These include affinity, efficacy, potency, number of occupied receptors, association and dissociation rates (i.e. residence time) and target accessibility.

This is a set of 20 slides suitable for beginners wishing to gain an understanding of the basic principles underlying receptor pharmacology. Provided by Prof. JA Peters, University of Dundee School of Medicine.

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Overview of types of receptors, their mechanisms of action and examples

Main types of drug targets and their mechanisms of action

Drug Target

Description

Example(s)

Receptors

Channel-linked receptors

Coupled directly to an ion channel. Activation opens the channel, making a cell membrane permeable to specific ions. These channels are known as ‘ligand-gated’ because it is receptor binding that operates them (in contrast to ‘voltage-gated’ channels that respond to changes in membrane potential) (see B in figure).

Nicotinic acetylcholine receptors;

gamma-Aminobutyric acid (GABA) receptors

G-Protein coupled receptors

Coupled to intracellular effector mechanisms via a family of closely related 'G‐proteins' that participate in signal transduction by coupling receptor binding to intracellular enzyme activation or the opening of an ion channel. Secondary messenger systems include the enzymes, adenylyl cyclase and guanylyl cyclase, which generate cyclic AMP and cyclic GMP, respectively (see A in figure).

Muscarinic acetylcholine receptors;

beta-Adrenoceptors;

Dopamine receptors;

5-hydroxytryptamine (Serotonin) receptors;

Opioid receptors

 

Kinase-linked receptors

Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions.

Insulin receptors

Nuclear hormone receptors

Intracellular and also known as 'nuclear receptors’. Binding of a ligand promotes or inhibits synthesis of new proteins, which may take hours or days to promote a biological effect.

Steroid hormone receptors;

Thyroid hormone receptors;

Vitamin D receptors

Other targets

Voltage-sensitive ion channels

Found in excitable tissues and a potential target for drugs that can block the channel or interfere with conductance in other ways.

Na+ channels that are blocked by local anesthetics such as lidocaine

Enzymes

Catalyze biochemical reactions, some of which involve the production of key mediators of physiological processes in body systems. Drugs interfere with the active site of the enzyme or affect co‐factors required by the enzyme for activity. In most cases inhibition of the active site is competitive although in some cases it may be long-lasting and effectively irreversible (e.g. aspirin) (see C in figure)

Inhibitors of cyclooxygenase such as aspirin;

Inhibitors of angiotensin converting enzyme such as  enalapril;

Inhibitors of xanthine oxidase such as allopurinol

Transporter proteins

Specialized proteins that carry ions or molecules across cell membranes. Movement may be in either direction, and may involve exchange of one substance for another, co-transport of two or more substances in the same direction, or ‘pumping’ of a single substance into or out of a cell or organelle. Drugs may act on transporters to inhibit their activity or may also act as ‘false substrates’, preventing the transport of the normal biological substrate (see D in figure).

Inhibitors of serotonin reuptake transporter such as fluoxetine

Cell adhesion proteins

Type-1 membrane glycoproteins that mediate cell-cell and cell-matrix adhesion by acting as transmembrane linkers to connect ligands on the outside of the cell (other cell membrane molecules, ECM components) to the actin cytoskeleton. Includes the adherins and integrins.

β2 integrins on leukocytes which are essential for effective immune responses. Adhesion class GPCRs. Cadherins such as E-cadherin required for endothelial cell-cell contact, and tissue morphogenesis during embryonic development.

Average: 3.5 (11 votes)

Main types of drug targets and their mechanisms of action

Drug Target

Description

Example(s)

Receptors

Channel-linked receptors

Coupled directly to an ion channel. Activation opens the channel, making a cell membrane permeable to specific ions. These channels are known as ‘ligand-gated’ because it is receptor binding that operates them (in contrast to ‘voltage-gated’ channels that respond to changes in membrane potential) (see B in figure).

Nicotinic acetylcholine receptors;

gamma-Aminobutyric acid (GABA) receptors

G-Protein coupled receptors

Coupled to intracellular effector mechanisms via a family of closely related 'G‐proteins' that participate in signal transduction by coupling receptor binding to intracellular enzyme activation or the opening of an ion channel. Secondary messenger systems include the enzymes, adenylyl cyclase and guanylyl cyclase, which generate cyclic AMP and cyclic GMP, respectively (see A in figure).

Muscarinic acetylcholine receptors;

beta-Adrenoceptors;

Dopamine receptors;

5-hydroxytryptamine (Serotonin) receptors;

Opioid receptors

 

Kinase-linked receptors

Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions.

Insulin receptors

Nuclear hormone receptors

Intracellular and also known as 'nuclear receptors’. Binding of a ligand promotes or inhibits synthesis of new proteins, which may take hours or days to promote a biological effect.

Steroid hormone receptors;

Thyroid hormone receptors;

Vitamin D receptors

Other targets

Voltage-sensitive ion channels

Found in excitable tissues and a potential target for drugs that can block the channel or interfere with conductance in other ways.

Na+ channels that are blocked by local anesthetics such as lidocaine

Enzymes

Catalyze biochemical reactions, some of which involve the production of key mediators of physiological processes in body systems. Drugs interfere with the active site of the enzyme or affect co‐factors required by the enzyme for activity. In most cases inhibition of the active site is competitive although in some cases it may be long-lasting and effectively irreversible (e.g. aspirin) (see C in figure)

Inhibitors of cyclooxygenase such as aspirin;

Inhibitors of angiotensin converting enzyme such as  enalapril;

Inhibitors of xanthine oxidase such as allopurinol

Transporter proteins

Specialized proteins that carry ions or molecules across cell membranes. Movement may be in either direction, and may involve exchange of one substance for another, co-transport of two or more substances in the same direction, or ‘pumping’ of a single substance into or out of a cell or organelle. Drugs may act on transporters to inhibit their activity or may also act as ‘false substrates’, preventing the transport of the normal biological substrate (see D in figure).

Inhibitors of serotonin reuptake transporter such as fluoxetine

Cell adhesion proteins

Type-1 membrane glycoproteins that mediate cell-cell and cell-matrix adhesion by acting as transmembrane linkers to connect ligands on the outside of the cell (other cell membrane molecules, ECM components) to the actin cytoskeleton. Includes the adherins and integrins.

β2 integrins on leukocytes which are essential for effective immune responses. Adhesion class GPCRs. Cadherins such as E-cadherin required for endothelial cell-cell contact, and tissue morphogenesis during embryonic development.

Average: 2.7 (10 votes)

Main types of drug targets and their mechanisms of action

Drug Target

Description

Example(s)

Receptors

Channel-linked receptors

Coupled directly to an ion channel. Activation opens the channel, making a cell membrane permeable to specific ions. These channels are known as ‘ligand-gated’ because it is receptor binding that operates them (in contrast to ‘voltage-gated’ channels that respond to changes in membrane potential) (see B in figure).

Nicotinic acetylcholine receptors;

gamma-Aminobutyric acid (GABA) receptors

G-Protein coupled receptors

Coupled to intracellular effector mechanisms via a family of closely related 'G‐proteins' that participate in signal transduction by coupling receptor binding to intracellular enzyme activation or the opening of an ion channel. Secondary messenger systems include the enzymes, adenylyl cyclase and guanylyl cyclase, which generate cyclic AMP and cyclic GMP, respectively (see A in figure).

Muscarinic acetylcholine receptors;

beta-Adrenoceptors;

Dopamine receptors;

5-hydroxytryptamine (Serotonin) receptors;

Opioid receptors

 

Kinase-linked receptors

Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions.

Insulin receptors

Nuclear hormone receptors

Intracellular and also known as 'nuclear receptors’. Binding of a ligand promotes or inhibits synthesis of new proteins, which may take hours or days to promote a biological effect.

Steroid hormone receptors;

Thyroid hormone receptors;

Vitamin D receptors

Other targets

Voltage-sensitive ion channels

Found in excitable tissues and a potential target for drugs that can block the channel or interfere with conductance in other ways.

Na+ channels that are blocked by local anesthetics such as lidocaine

Enzymes

Catalyze biochemical reactions, some of which involve the production of key mediators of physiological processes in body systems. Drugs interfere with the active site of the enzyme or affect co‐factors required by the enzyme for activity. In most cases inhibition of the active site is competitive although in some cases it may be long-lasting and effectively irreversible (e.g. aspirin) (see C in figure)

Inhibitors of cyclooxygenase such as aspirin;

Inhibitors of angiotensin converting enzyme such as  enalapril;

Inhibitors of xanthine oxidase such as allopurinol

Transporter proteins

Specialized proteins that carry ions or molecules across cell membranes. Movement may be in either direction, and may involve exchange of one substance for another, co-transport of two or more substances in the same direction, or ‘pumping’ of a single substance into or out of a cell or organelle. Drugs may act on transporters to inhibit their activity or may also act as ‘false substrates’, preventing the transport of the normal biological substrate (see D in figure).

Inhibitors of serotonin reuptake transporter such as fluoxetine

Cell adhesion proteins

Type-1 membrane glycoproteins that mediate cell-cell and cell-matrix adhesion by acting as transmembrane linkers to connect ligands on the outside of the cell (other cell membrane molecules, ECM components) to the actin cytoskeleton. Includes the adherins and integrins.

β2 integrins on leukocytes which are essential for effective immune responses. Adhesion class GPCRs. Cadherins such as E-cadherin required for endothelial cell-cell contact, and tissue morphogenesis during embryonic development.

Average: 2.5 (2 votes)

Main types of drug targets and their mechanisms of action

Drug Target

Description

Example(s)

Receptors

Channel-linked receptors

Coupled directly to an ion channel. Activation opens the channel, making a cell membrane permeable to specific ions. These channels are known as ‘ligand-gated’ because it is receptor binding that operates them (in contrast to ‘voltage-gated’ channels that respond to changes in membrane potential) (see B in figure).

Nicotinic acetylcholine receptors;

gamma-Aminobutyric acid (GABA) receptors

G-Protein coupled receptors

Coupled to intracellular effector mechanisms via a family of closely related 'G‐proteins' that participate in signal transduction by coupling receptor binding to intracellular enzyme activation or the opening of an ion channel. Secondary messenger systems include the enzymes, adenylyl cyclase and guanylyl cyclase, which generate cyclic AMP and cyclic GMP, respectively (see A in figure).

Muscarinic acetylcholine receptors;

beta-Adrenoceptors;

Dopamine receptors;

5-hydroxytryptamine (Serotonin) receptors;

Opioid receptors

 

Kinase-linked receptors

Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions.

Insulin receptors

Nuclear hormone receptors

Intracellular and also known as 'nuclear receptors’. Binding of a ligand promotes or inhibits synthesis of new proteins, which may take hours or days to promote a biological effect.

Steroid hormone receptors;

Thyroid hormone receptors;

Vitamin D receptors

Other targets

Voltage-sensitive ion channels

Found in excitable tissues and a potential target for drugs that can block the channel or interfere with conductance in other ways.

Na+ channels that are blocked by local anesthetics such as lidocaine

Enzymes

Catalyze biochemical reactions, some of which involve the production of key mediators of physiological processes in body systems. Drugs interfere with the active site of the enzyme or affect co‐factors required by the enzyme for activity. In most cases inhibition of the active site is competitive although in some cases it may be long-lasting and effectively irreversible (e.g. aspirin) (see C in figure)

Inhibitors of cyclooxygenase such as aspirin;

Inhibitors of angiotensin converting enzyme such as  enalapril;

Inhibitors of xanthine oxidase such as allopurinol

Transporter proteins

Specialized proteins that carry ions or molecules across cell membranes. Movement may be in either direction, and may involve exchange of one substance for another, co-transport of two or more substances in the same direction, or ‘pumping’ of a single substance into or out of a cell or organelle. Drugs may act on transporters to inhibit their activity or may also act as ‘false substrates’, preventing the transport of the normal biological substrate (see D in figure).

Inhibitors of serotonin reuptake transporter such as fluoxetine

Cell adhesion proteins

Type-1 membrane glycoproteins that mediate cell-cell and cell-matrix adhesion by acting as transmembrane linkers to connect ligands on the outside of the cell (other cell membrane molecules, ECM components) to the actin cytoskeleton. Includes the adherins and integrins.

β2 integrins on leukocytes which are essential for effective immune responses. Adhesion class GPCRs. Cadherins such as E-cadherin required for endothelial cell-cell contact, and tissue morphogenesis during embryonic development.

Average: 1.5 (2 votes)

Receptor Affinity

Affinity of ligands is a function of both the rate of association and the rate of dissociation of the ligand–receptor complex; the former depends on the 'goodness of fit' at a molecular level, whereas the latter depends on how tightly the ligand is bound (the strength of the chemical bond). Systems requiring rapid fine modulation (e.g. nerve synapses) must have agonists with a low receptor affinity because those with high receptor affinity would produce unnecessarily prolonged responses. During stimulation, agonist concentration near the receptor must be relatively high, but the agonist is then cleared rapidly by active transport. In contrast, growth factors are typically peptides with very high affinity for their receptors, and achieve their effects at concentrations that are difficult to detect in vivo. Some drug–receptor interactions are so strong that they are effectively irreversible. A good example is aspirin, which irreversibly inhibits its target, the enzyme cyclooxygenase.

Agonist affinity can be measured in terms of a dissociation constant for agonist binding to a receptor using ligand binding or functional assays. In such systems, however, measurements of affinity are contaminated by efficacy. In this 11-page review, the author describes methods to assess affinity and efficacy at G protein-coupled receptors using experimental approaches to separate the two parameters. This article would be appropriate for a student in pharmacology who has extensive knowledge of receptor theory and G protein-coupled receptors. 

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Affinity of ligands is a function of both the rate of association and the rate of dissociation of the ligand–receptor complex; the former depends on the 'goodness of fit' at a molecular level, whereas the latter depends on how tightly the ligand is bound (the strength of the chemical bond). Systems requiring rapid fine modulation (e.g. nerve synapses) must have agonists with a low receptor affinity because those with high receptor affinity would produce unnecessarily prolonged responses. During stimulation, agonist concentration near the receptor must be relatively high, but the agonist is then cleared rapidly by active transport. In contrast, growth factors are typically peptides with very high affinity for their receptors, and achieve their effects at concentrations that are difficult to detect in vivo. Some drug–receptor interactions are so strong that they are effectively irreversible. A good example is aspirin, which irreversibly inhibits its target, the enzyme cyclooxygenase.

This review of approximately 1700 words defines affinity and walks learners through the equations for calculation of binding affinity from a chemistry approach. This topic is more appropriate for advanced learners in pharmacology.

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Affinity of ligands is a function of both the rate of association and the rate of dissociation of the ligand–receptor complex; the former depends on the 'goodness of fit' at a molecular level, whereas the latter depends on how tightly the ligand is bound (the strength of the chemical bond). Systems requiring rapid fine modulation (e.g. nerve synapses) must have agonists with a low receptor affinity because those with high receptor affinity would produce unnecessarily prolonged responses. During stimulation, agonist concentration near the receptor must be relatively high, but the agonist is then cleared rapidly by active transport. In contrast, growth factors are typically peptides with very high affinity for their receptors, and achieve their effects at concentrations that are difficult to detect in vivo. Some drug–receptor interactions are so strong that they are effectively irreversible. A good example is aspirin, which irreversibly inhibits its target, the enzyme cyclooxygenase.

Agonists, antagonists, and partial agonists

Receptor ligands can be distinguished on the basis of their potential to initiate a biological response following receptor binding:

Agonists bind to a receptor protein to produce a conformational change, which is necessary to initiate a signal that is coupled to a biological response. As the free ligand concentration increases, so does the proportion of receptors occupied, and hence the biological effect. When all of the receptors are occupied the maximum biological effect is achieved. It has been observed in many receptor systems that full agonists can elicit the maximum effect without occupying all available receptors, suggesting the concept of ‘spare receptors’. This apparent excess of receptors allows full responses to occur at lower ligand concentrations than would otherwise be required.

Antagonists bind to a receptor but do not produce the conformational change that initiates an intracellular signal. Occupation of the receptor by a competitive antagonist prevents binding of other ligand and so 'antagonizes' the biological response to the agonist. The inhibition that antagonists produce can be overcome by increasing the dose of the agonist. Some antagonists interfere with the response to the agonist in other ways than receptor competition and are known as non-competitive antagonists. Simply increasing the dose of the agonist cannot overcome their effects and so the maximum response to the agonist (its 'efficacy') is reduced.

Partial agonists are able to activate a receptor but cannot produce a maximal signaling effect equivalent to that of a full agonist even when all available receptors are occupied. When mixed with full agonists, partial agonists block receptor sites that could potentially be occupied by the full agonist, which reduces the overall response (i.e. they seem to antagonize the effect of the full agonist). Partial agonists have some advantages as therapeutic agents. Although they are unable to achieve the same maximum effect as the full agonist, they are less likely to produce receptor-mediated adverse effects at the top of their dose–response curve (e.g. the partial opioid receptor agonist buprenorphine does not cause as much respiratory depression as morphine when it is used as an analgesic).

Inverse agonists produce the opposite effect to the full agonist when they bind to a receptor. For inverse agonists to be identified, the relevant endogenous receptor must show some degree of coupling to a biological response even in the absence of ligand binding (i.e. constitutive activity). Many receptors possess constitutive activity.

This approximately 4.5 minute video defines the terms agonist and antagonist using acetylcholine and curare, respectively, as examples. The video provides easy to understand definitions of the terms with a relevant example.

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Receptor ligands can be distinguished on the basis of their potential to initiate a biological response following receptor binding:

Agonists bind to a receptor protein to produce a conformational change, which is necessary to initiate a signal that is coupled to a biological response. As the free ligand concentration increases, so does the proportion of receptors occupied, and hence the biological effect. When all of the receptors are occupied the maximum biological effect is achieved. It has been observed in many receptor systems that full agonists can elicit the maximum effect without occupying all available receptors, suggesting the concept of ‘spare receptors’. This apparent excess of receptors allows full responses to occur at lower ligand concentrations than would otherwise be required.

Antagonists bind to a receptor but do not produce the conformational change that initiates an intracellular signal. Occupation of the receptor by a competitive antagonist prevents binding of other ligand and so 'antagonizes' the biological response to the agonist. The inhibition that antagonists produce can be overcome by increasing the dose of the agonist. Some antagonists interfere with the response to the agonist in other ways than receptor competition and are known as non-competitive antagonists. Simply increasing the dose of the agonist cannot overcome their effects and so the maximum response to the agonist (its 'efficacy') is reduced.

Partial agonists are able to activate a receptor but cannot produce a maximal signaling effect equivalent to that of a full agonist even when all available receptors are occupied. When mixed with full agonists, partial agonists block receptor sites that could potentially be occupied by the full agonist, which reduces the overall response (i.e. they seem to antagonize the effect of the full agonist). Partial agonists have some advantages as therapeutic agents. Although they are unable to achieve the same maximum effect as the full agonist, they are less likely to produce receptor-mediated adverse effects at the top of their dose–response curve (e.g. the partial opioid receptor agonist buprenorphine does not cause as much respiratory depression as morphine when it is used as an analgesic).

Inverse agonists produce the opposite effect to the full agonist when they bind to a receptor. For inverse agonists to be identified, the relevant endogenous receptor must show some degree of coupling to a biological response even in the absence of ligand binding (i.e. constitutive activity). Many receptors possess constitutive activity.

This is a comprehensive introduction to basic principles of pharmacology. It is designed as a just-in-time-teaching lesson which is appropriate for any beginning students of pharmacology. This approximately 5000-word essay covers all topics expected to be discussed in an overview of the basic principles including receptors, agonists and antagonists, dose-response relationships, quantal dose-response, additive and synergistic effects, desensitization and therapeutic index.

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