Receptor (biochemistry)

1. Ligands
2. Receptors
3. Secondary Messengers
These are examples of membrane receptors.

In biochemistry and pharmacology, a receptor is a protein-molecule that receives chemical-signals from outside a cell. When such chemical-signals bind to a receptor, they cause some form of cellular/tissue-response, e.g. a change in the electrical-activity of a cell. In this sense, a receptor is a protein-molecule that recognises and responds to endogenous-chemical signals, e.g. an acetylcholine-receptor recognizes and responds to its endogenous-ligand, acetylcholine. However, sometimes in pharmacology, the term is also used to include other proteins that are drug-targets, such as enzymes, transporters and ion-channels.

Receptor-proteins are embedded in all cells' plasmatic-membranes; facing extracellular-(cell surface receptors), cytoplasmic (cytoplasmic-receptors), or in the nucleus (nuclear receptors). A molecule that binds to a receptor is called a ligand, and can be a peptide (short-protein) or another small molecule such as a neurotransmitter, hormone, pharmaceutical-drug, toxin, or parts of the outside of a virus or microbe. The endogenously designated-molecule for a particular receptor is referred to as its endogenous-ligand. E.g. the endogenous-ligand for the nicotinic-acetylcholine receptor is acetylcholine but the receptor can also be activated by nicotine and blocked by curare.

Each receptor is linked to a specific cellular-biochemical pathway. While numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure, much like how locks will only accept specifically shaped-keys. When a ligand binds to its corresponding receptor, it activates or inhibits the receptor's associated-biochemical pathway.

Structure

Transmembrane receptor:E=extracellular space; I=intracellular space; P=plasma membrane

The structures of receptors are very diverse and can broadly be classified into the following categories:

• Type 1: L (ionotropic-receptors)– These receptors are typically the targets of fast-neurotransmitters such as acetylcholine (nicotinic) and GABA; and, activation of these receptors results in changes in ion-movement across a membrane. They have a hetero-structure. Each subunit consists of the extracellular-ligand-binding domain and a transmembrane-domain where the transmembrane-domain in turn includes four transmembrane-alpha helixes. The ligand-binding cavities are located at the interface between the subunits.
• Type 2: G protein-coupled receptors (metabotropic) – This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e.g. dopamine, metabotropic-glutamate. They are composed of seven transmembrane-alpha helices. The loops connecting the alpha-helices form extracellular and intracellular-domains. The binding-site for larger peptidic-ligands is usually located in the extracellular-domain whereas the binding-site for smaller non-peptidic ligands is often located between the seven alpha-helices and one extracellular-loop.^[1] The aforementioned receptors are coupled to different intracellular-effector systems via G-proteins.^[2]
• Type 3: kinase linked and related receptors (see "Receptor tyrosine kinase", and "Enzyme-linked receptor") - They are composed of an extracellular-domain containing the ligand-binding site and an intracellular-domain, often with enzymatic-function, linked by a single transmembrane-alpha helix. e.g. the insulin-receptor.
• Type 4: nuclear receptors – While they are called nuclear-receptors, they are actually located in the cytosol and migrate to the nucleus after binding with their ligands. They are composed of a C-terminal-ligand-binding region, a core-DNA-binding domain (DBD) and an N-terminal-domain that contains the AF1(activation function 1) region. The core-region has two zinc-fingers that are responsible for recognising the DNA-sequences specific to this receptor. The N-terminal interacts with other cellular-transcription factors in a ligand-independent manner; and, depending on these interactions it can modify the binding/activity of the receptor. Steroid and thyroid-hormone receptors are examples of such receptors.^[3]

Membrane-receptors may be isolated from cell-membranes by complex-extraction procedures using solvents, detergents, and/or affinity purification.

The structures and actions of receptors may be studied by using biophysical-methods such as X-ray crystallography, NMR, circular dichroism, and dual polarisation interferometry. Computer simulations of the dynamic-behavior of receptors have been used to gain understanding of their mechanisms of action.

Binding and activation

Ligand-binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action.

$\left[\mathrm{Ligand}\right] \cdot \left[\mathrm{Receptor}\right]\;\;\overset{K_d}{\rightleftharpoons}\;\;\left[\text{Ligand-receptor complex}\right]$

(the brackets stand for concentrations

One measure of how well a molecule fits a receptor is its binding-affinity, which is inversely related to the dissociation constant K_d. A good fit corresponds with high affinity and low K_d. The final biological-response (e.g. second messenger cascade, muscle-contraction), is only achieved after a significant number of receptors are activated.

Affinity is a measure of the tendency of a ligand to bind to its receptor. Efficacy is the measure of the bound-ligand to activate its receptor.

Agonists versus antagonists

Efficacy spectrum of receptor ligands.

Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist:

• (Full) agonists are able to activate the receptor and result in a maximal-biological response. The natural endogenous-ligand with the greatest efficacy for a given receptor is by definition a full-agonist (100% efficacy).
• Partial agonists do not activate receptors with maximal-efficacy, even with maximal binding, causing responses which are partial compared to those of full-agonists (efficacy between 0 and 100%).
• Antagonists bind to receptors but do not activate them. This results in a receptor-blockade, inhibiting the binding of agonists and inverse-agonists. Receptor-antagonists can be competitive (or reversible), and compete with the agonist for the receptor, or they can be irreversible-antagonists that form covalent-bonds with the receptor and completely block it. The protein-pump inhibitor omeprazole is an example of an irreversible-antagonist. The effects of irreversible antagonism can only be reversed by synthesis of new receptors.
• Inverse-agonists reduce the activity of receptors by inhibiting their constitutive-activity (negative-efficacy).
• Allosteric-modulators: They do not bind to the agonist-binding site of the receptor but instead on specific allosteric-binding sites, through which they modify the effect of the agonist, e.g. benzodiazepines (BZDs) bind to the BZD-site on the GABA-A receptor and potentiate the effect of endogenous-GABA.

Note that the idea of receptor-agonism and antagonism only refers to the interaction between receptors and ligands and not to their biological-effects.

Constitutive-activity

A receptor which is capable of producing a biological-response in the absence of a bound-ligand is said to display "constitutive-activity".^[4] The constitutive-activity of a receptor may be blocked by an inverse agonist. The anti-obesity drugs rimonabant and tarannabant are inverse-agonists at the cannabinoid-CB1 receptor and though they produced significant weight-loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive-activity of the cannabinoid-receptor.

Mutations in receptors that result in increased constitutive-activity underlie some inherited-diseases, such as precocious-puberty (due to mutations in luteinizing-hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors).

Theories of drug-receptor interaction

Occupation-theory

The central-dogma of receptor-pharmacology is that a drug-effect is directly proportional to the number of receptors that are occupied. Furthermore, a drug effect ceases as a drug-receptor complex dissociates.

Ariëns & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of ligands bound to receptors.^[5][6]

• Affinity: The ability of a drug to combine with a receptor to create a drug-receptor complex.
• Efficacy: The ability of a drug-receptor complex to initiate a response.

Rate-theory

In contrast to the accepted occupation-theory, rate-theory proposes that the activation of receptors is directly proportional to the total number of encounters of a drug with its receptors per unit-time. Pharmacological-activity is directly proportional to the rates of dissociation and association, not the number of receptors occupied:^[7]

• Agonist: A drug with a fast association and a fast dissociation.
• Partial-agonist: A drug with an intermediate-association and an intermediate-dissociation.
• Antagonist: A drug with a fast-association & slow-dissociation

Induced-fit theory

As a drug approaches a receptor, the receptor alters the conformation of its binding-site to produce drug—receptor complex.

Spare-receptors

In some receptor-systems e.g. acetylcholine at the neuromuscular-junction in smooth-muscle, agonists are able to elicit maximal-response at very low-levels of receptor-occupancy (<1%). Thus that system has spare-receptors or a receptor-reserve. This arrangement produces an economy of neurotransmitter-production and release.^[3]

Receptor-regulation

Cells can increase (upregulate) or decrease (downregulate) the number of receptors to a given hormone or neurotransmitter to alter their sensitivity to different molecule. This is a locally acting feedback mechanism.

• Change in the receptor conformation such that binding of the agonist does not activate the receptor. This is seen with ion channel receptors.
• Uncoupling of the receptor effector molecules is seen with G-protein couple receptor.
• Receptor sequestration (internalization).^[8] e.g. in the case of hormone receptors.

Ligands

The ligands for receptors are as diverse as their receptors. Examples include:^[9]

Extracellular

Receptor	Ligand	Ion current
Nicotinic acetylcholine receptor	Acetylcholine, Nicotine	Na^+, K^+, Ca^2+[9]
Glycine receptor (GlyR)	Glycine, Strychnine	Cl^− > HCO^−3 [9]
GABA receptors: GABA-A, GABA-C	GABA	Cl^− > HCO^−3 [9]
Glutamate receptors: NMDA receptor, AMPA receptor, and Kainate receptor	Glutamate	Na^+, K^+, Ca^2+ [9]
5-HT3 receptor	Serotonin	Na^+, K^+ [9]
P2X receptors	ATP	Ca^2+, Na^+, Mg^2+ [9]

Intracellular

Receptor	Ligand	Ion current
cyclic nucleotide-gated ion channels	cGMP (vision), cAMP and cGTP (olfaction)	Na^+, K^+ [9]
IP3 receptor	IP3	Ca^2+ [9]
Intracellular ATP receptors	ATP (closes channel)[9]	K^+ [9]
Ryanodine receptor	Ca^2+	Ca^2+ [9]

Role in genetic disorders

Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the hormone is produced at decreased level; this gives rise to the "pseudo-hypo-" group of endocrine disorders, where there appears to be a decreased hormonal level while in fact it is the receptor that is not responding sufficiently to the hormone.

In the immune system

The main receptors in the immune system are pattern recognition receptors (PRRs), toll-like receptors (TLRs), killer activated and killer inhibitor receptors (KARs and KIRs), complement receptors, Fc receptors, B cell receptors and T cell receptors.^[10]

See also

• K_i Database
• Ion channel linked receptors
• Neuropsychopharmacology
• Schild regression for ligand receptor inhibition
• Signal transduction
• Stem cell marker
• Wikipedia:MeSH D12.776#MeSH D12.776.543.750 – receptors.2C cell surface

References

1. Congreve M, Marshall F (March 2010). "The impact of GPCR structures on pharmacology and structure-based drug design". Br. J. Pharmacol. 159 (5): 986–96. doi:10.1111/j.1476-5381.2009.00476.x. PMC: 2839258. PMID 19912230.
2. Kou Qin, Chunmin Dong, Guangyu Wu & Nevin A Lambert (August 2011). "Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers". Nature Chemical Biology 7 (11): 740–747. doi:10.1038/nchembio.642. PMC: 3177959. PMID 21873996.
3. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G (2012). Rang & Dale's Pharmacology (7th ed.). Elsevier Churchill Livingstone. ISBN 978-0-7020-3471-8.
4. Milligan G (December 2003). "Constitutive activity and inverse agonists of G protein coupled receptors: a current perspective". Mol. Pharmacol. 64 (6): 1271–6. doi:10.1124/mol.64.6.1271. PMID 14645655.
5. Ariens EJ (September 1954). "Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory". Arch Int Pharmacodyn Ther 99 (1): 32–49. PMID 13229418.
6. Stephenson RP (December 1956). "A modification of receptor theory". Br J Pharmacol Chemother 11 (4): 379–93. doi:10.1111/j.1476-5381.1956.tb00006.x. PMC: 1510558. PMID 13383117.
7. Silverman RB (2004). "3.2.C Theories for Drug—Receptor Interactions". The Organic Chemistry of Drug Design and Drug Action (2nd ed.). Amsterdam: Elsevier Academic Press. ISBN 0-12-643732-7.
8. Boulay G, Chrétien L, Richard DE, Guillemette G (November 1994). "Short-term desensitization of the angiotensin II receptor of bovinde adrenal glomerulosa cells corresponds to a shift from a high to low affinity state". Endocrinology 135 (5): 2130–6. doi:10.1210/en.135.5.2130.
9. Boulpaep, EL; Boron WF (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 90. ISBN 1-4160-2328-3.
10. Waltenbaugh C, Doan T, Melvold R, Viselli S (2008). Immunology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 20. ISBN 0-7817-9543-5.

External links

• IUPHAR GPCR Database and Ion Channels Compendium
• Human plasma membrane receptome
• Cell surface receptors at the US National Library of Medicine Medical Subject Headings (MeSH)