Receptor (biochemistry)

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For other uses, see Receptor (disambiguation).
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[edit]

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[edit]

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

(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 Kd. A good fit corresponds with high affinity and low Kd. 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[edit]

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[edit]

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[edit]

Occupation-theory[edit]

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[edit]

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[edit]

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

Spare-receptors[edit]

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[edit]

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[edit]

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

Extracellular[edit]

Receptor Ligand Ion current
Nicotinic acetylcholine receptor Acetylcholine, Nicotine Na+, K+, Ca2+[9]
Glycine receptor (GlyR) Glycine, Strychnine Cl > HCO3 [9]
GABA receptors: GABA-A, GABA-C GABA Cl > HCO3 [9]
Glutamate receptors: NMDA receptor, AMPA receptor, and Kainate receptor Glutamate Na+, K+, Ca2+ [9]
5-HT3 receptor Serotonin Na+, K+ [9]
P2X receptors ATP Ca2+, Na+, Mg2+ [9]

Intracellular[edit]

Receptor Ligand Ion current
cyclic nucleotide-gated ion channels cGMP (vision), cAMP and cGTP (olfaction) Na+, K+ [9]
IP3 receptor IP3 Ca2+ [9]
Intracellular ATP receptors ATP (closes channel)[9] K+ [9]
Ryanodine receptor Ca2+ Ca2+ [9]

Role in genetic disorders[edit]

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[edit]

Main article: Immune receptor

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[edit]

References[edit]

  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. ^ a b 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. ^ a b c d e f g h i j k l 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[edit]