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.

http://www.slideshare.net/PharmacologyEducationProject/introductory-receptor-pha…

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.

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.

Mechanism of drug action

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.

Receptors: Definition, types, structure, function

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.

Receptor pharmacology

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.

Drug receptor interactions

MSD Manual for the Professional (formerly Merck's Manual)

By Abimbola Farinde, PhD, PharmD, Columbia Southern University, Orange Beach, AL

A nuclear receptor: Farnesoid X Receptor (FXR)

Farnesoid X Receptor (FXR), also known as NR1H4 (nuclear receptor subfamily 1, group H, member 4), is the nuclear receptor for bile acids (BAs), its endogenous ligands (from which the initial name “BAR” - bile acid receptor). The membrane G-protein coupled receptor TGR5 (GPBAR1) is the second major signaling pathway for the BAs, being highly expressed in the gallbladder and intestine but not in hepatocytes. Rodents and humans have a unique FXR gene that encodes, by alternative splicing, four isoforms of the FXR protein, actually identified as α1, α2, α3, and α4. A second FXR gene activated by lanosterol was found in mice (FXRβ) but it is a pseudogene in humans.

FXR is predominantly expressed along the gastrointestinal tract, including the liver, gallbladder, small intestine, and colon, but is also present in high amounts in kidneys; it is also expressed in adrenal glands, ovaries, and pancreatic beta-cells, albeit at much lower levels compared to liver. BAs, both primary (CA, CDCA) and secondary (DCA, LCA) are the physiological ligands of FXR, the CDCA having the highest activation potency (EC₅₀ ~50μM), while LCA and DCA are weak activators. The other two naturally occurring molecules, guggulsterone and oleanolic acid are antagonists of FXR. Synthetic molecules like GW4064, obeticholic acid, 6-ethyl-CDCA, fexaramine, fexarine, WAY-362450, or T0901317 are highly potent selective FXR agonists (EC₅₀ <100 nM).

Upon activation, FXR binds to specific DNA sequences – FXRE (FXR responsive elements), located on the promoters of target genes. FXR can control the transcription of its target genes by binding to a variety of FXRE, either as a monomer or as a heterodimer with the nuclear receptor RXR (retinoid X receptor). For instance, FXR transactivates the UGT2B4 gene or trans-represses the transcription of ApoAI, by binding as monomer to an atypical FXRE. By binding as heterodimer FXR/RXR to an IR-1 sequence, FXR transactivates the PLTP gene but suppresses the transcription of ApoCIII.

FXR plays a major role in regulating bile acid metabolism at all levels. For instance, FXR represses the expression of CYP7A1 and CYP8B1, the two major enzymes involved in BA hepatic biosynthesis. FXR directly regulates the transcription of BSEP gene, the major canalicular BA transporter, thus protecting the liver from cholestasis; also, MDR3/ABCB4 and MRP2/ABCC2, responsible for hepatobiliary transport of phospholipids and hydrophilic organic anions, respectively are upregulated by FXR, while the NTCP transporter necessary for BA uptake is downregulated by FXR in the sinusoidal membrane.

FXR is one of the major nuclear receptors that regulate genes involved in lipid absorption, excretion, and metabolism. A major pathway is the inhibition of the hepatic de novo lipogenesis via the trans-repression of SREBP-1c and its lipogenic genes. Also, FXR may decrease TG accumulation by promoting the β-oxidation of fatty acids through the direct regulation of the PPARα gene (PPARA). FXR also controls the clearance of circulating apolipoproteins like ApoCII, ApoCIII, and ANGPTL3.

FXR impacts glucose homeostasis too, by regulating hepatic glucose metabolism, glycogen synthesis and storage, glucose absorption at the intestinal level, insulin sensitivity (mainly in adipocytes and liver) and insulin secretion by pancreatic beta-cells.

Iuliana Popescu, University of Kentucky

GPCRs: Opioid receptors

RECEPTOR	GENE	TISSUE EXPRESSION	G PROTEIN TRANSDUCER/INTRACELLULAR RESPONSE	ENDOGENOUS LIGANDS
Mu (μ) opioid receptor, MOR	OPRM1	Brain, spinal cord, peripheral sensory neurons, gastrointestinal tract	G_i/o/ adenylyl cyclase inhibition, ↓cAMP	β-endorphin*, [Leu]enkephalin, [Met]enkephalin
Delta (δ) opioid receptor, DOR	OPRD1	Brain, peripheral sensory neurons	G_i/o / adenylyl cyclase inhibition, ↓cAMP	β-endorphin, [Leu]enkephalin, [Met]enkephalin
Kappa (κ) opioid receptor, KOR	OPRK1	Brain, spinal cord, peripheral sensory neurons, gastrointestinal tract	G_i/o / adenylyl cyclase inhibition, ↓cAMP	big dynorphin, dynorphin A
Nociceptin receptor, NOR	OPRL1	Brain, spinal cord	G_i/o / adenylyl cyclase inhibition, ↓cAMP	nociceptin/orphanin FQ
*highest potency endogenous μ opioid receptor agonist

The 4 human opioid receptors are inhibitory G protein-coupled receptors that are part of a neuromodulatory system that regulates reward, aversion and mood, and modulates pain sensation (nociception). The endogenous opioid receptor agonists are the peptide ligands β-endorphin, enkephalins, dynorphins and nociceptin/orphanin FQ. In general β-endorphin and the enkephalins are high affinity agonists for their receptors and the dynorphins have lower affinities.

To varying degrees, depending on ligand selectivity, this family of receptors are the targets of semisynthetic and synthetic opioids that are used as drugs (both therapeutically and illicitly).

The analgesic effect of clinically used opioids is principally mediated by the μ opioid receptor. Unfortunately, the μ opioid receptor is also the receptor that is responsible for the adverse actions of morphine (and other μ opioid receptor agonists). μ opioid receptor agonists induce tolerance, respiratory depression (the main cause of overdose) and drug dependence (contributing to addiction). Expression of μ opioid receptors in the gastrointestinal tract is responsible for opioid-induced constipation.

The ‘opioid epidemic’ has driven the rapid evolution of synthetic opioid derivatives (referred to as novel synthetic opioids or NSOs), such as non-pharmaceutical fentanyls and the 2-benzylbenzimidazole ('nitazene') class of non-fentanyl type agonists. Many of the novel derivatives are significantly more potent μ opioid receptor agonists than morphine and fentanyl, and subsequently they are highly addictive and are associated with a severe risk of fatal overdose.

With regard to the other opioid receptors, the δ opioid receptor has anxiolytic and antidepressant functions, and may modulate chronic pain nociception. The κ opioid receptor activation produces aversive and psychotomimetic effects (causing delusions/delirium), and mediates an antipruritic effect. The nociceptin receptor is involved in the regulation of instinctive and emotional behaviours. Despite high sequence identity with μ, δ and k opioid receptors, the nociceptin receptor has negligible affinity for opioid peptides or morphine-like compounds.

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.

Overview of agonists and antagonists

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.

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

Basic principles of pharmacology

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.