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 usually found embedded within the plasma membrane surface of a cell that receives chemical signals from outside the 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 the cell. In this sense, a receptor is a protein molecule that recognises and responds to endogenous chemical signals, e.g. the 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 the cell's plasma 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, or toxin. 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:

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 mechanism 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.

\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 the 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 the ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate the receptor.

Agonists versus antagonists[edit]

Efficacy spectrum of receptor ligands.

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

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

Constitutive activity[edit]

A receptor which is capable of producing its 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 drug effect is directly proportional to number of receptors occupied. Furthermore, drug effect ceases as drug-receptor complex dissociates.

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

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 the drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, not number of receptors occupied:[7]

Induced fit theory[edit]

As the drug approaches the 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 the system has spare receptors or 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 its sensitivity to this molecule. This is a locally acting feedback mechanism.

Ligands[edit]

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

Extracellular[edit]

ReceptorLigandIon current
Nicotinic acetylcholine receptorAcetylcholine, NicotineNa+, K+, Ca2+[9]
Glycine receptor (GlyR)Glycine, StrychnineCl > HCO3 [9]
GABA receptors: GABA-A, GABA-CGABACl > HCO3 [9]
Glutamate receptors: NMDA receptor, AMPA receptor, and Kainate receptorGlutamateNa+, K+, Ca2+ [9]
5-HT3 receptorSerotoninNa+, K+ [9]
P2X receptorsATPCa2+, Na+, Mg2+ [9]

Intracellular[edit]

ReceptorLigandIon current
cyclic nucleotide-gated ion channelscGMP (vision), cAMP and cGTP (olfaction)Na+, K+ [9]
IP3 receptorIP3Ca2+ [9]
Intracellular ATP receptorsATP (closes channel)[9]K+ [9]
Ryanodine receptorCa2+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. 

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