||This article may be too technical for most readers to understand. (May 2008)|
In the field of biochemistry, a receptor is a molecule usually found on the surface of a cell, that receives chemical signals from outside the cell. When such external substances bind to a receptor, they direct the cell to do something, such as divide, die, or allow specific substances to enter or exit the cell.
Receptors are proteins embedded in either the cell's plasma membrane (cell surface receptors), in the cytoplasm, or in the cell's nucleus (nuclear receptors), to which specific signaling molecules may attach. 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.
Numerous receptor types are found in a typical cell. Each type is linked to a specific biochemical pathway, and binds only certain ligand shapes, similarly to how locks require specifically shaped keys to open. When a ligand binds to its corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway.
Ligand binding changes the conformation (three-dimensional shape) of the receptor molecule. This alters the shape at a different part of the protein, changing the interaction of the receptor molecule with associated biochemicals, leading in turn to a cellular response mediated by the associated biochemical pathway. However, some ligands called antagonists merely block receptors from binding to other ligands without inducing any response themselves.
The structures of receptors are very diverse and can broadly be classified into the following categories:
- peripheral membrane proteins
- transmembrane proteins
- G protein-coupled receptors – 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
- ligand-gated ion channels – Have a heteropentameric structure. Each subunit of consist of the extracellular ligand-binding domain and a transmembrane domain where the transmembrane domain in turn includes four transmembrane alpha helixes.2 The ligand binding cavities are located at the interface between the subunits.
- receptor tyrosine kinase – Functional receptors are homodimers. Each monomer possesses a single transmembrane alpha helix and an extracellular domain containing the ligand binding cavity and an intracellular domain with catalytic activity.
- soluble globular proteins
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.
- (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.
The receptor-ligand affinity is greater than enzyme-substrate affinity.citation needed Whilst both interactions are specific and reversible, there is no chemical modification of the ligand as seen with the substrate upon binding to its enzyme.
Not every ligand that binds to a receptor also activates the 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 thoroughly, 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 receptor blockage, inhibiting the binding of agonists and inverse agonists.
- Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy).
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 receptors may be blocked by inverse agonist binding. 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).
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.
- Affinity: ability of the drug to combine with receptor to create drug-receptor complex
- Efficacy: ability of the drug-receptor complex to initiate a response
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
- Agonist: drug with fast association & fast dissociation
- Partial agonist: drug with intermediate association & intermediate dissociation
- Antagonist: drug with fast association & slow dissociation
As the drug approaches the receptor, the receptor alters the conformation of its binding site to produce drug—receptor complex.
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.
- Receptor desensitization8
- Uncoupling of receptor effector molecules.
- Receptor sequestration (internalization).8
Three types of transmembrane receptors can be classified into families based on the way they transmit information into the interior of the cell:9
- G protein-linked
- Ion channel-linked
Other transmembrane receptors include sigma receptors.
G protein-coupled receptors (GPCRs) are also known as seven transmembrane receptors or 7TM receptors, because they possess seven transmembrane alpha helices.12 Ligand activated GPCRs in turn activate an associated G-protein that in turn activates intracellular signaling cascades.
- Class A (or 1) (Rhodopsin-like)
- Class B (or 2) (Secretin receptor family)
- Class C (or 3) (Metabotropic glutamate/pheromone)
- Class D (or 4) (Fungal mating pheromone receptors)
- Class E (or 5) (Cyclic AMP receptors)
- Class F (or 6) (Frizzled/Smoothened)
Ligand gated ion channels also known as ionotropic receptors are heteromeric or homomeric oligomers.17 Binding of a ligand to the ion channel results in opening of the channel to increase ion flow through the channel or closing to decrease ion flow.
These receptors detect ligands through their extracellular domain and propagate signals via the tyrosine kinase of their intracellular domains. This family of receptors includes;
- Erythropoietin receptor (Erythropoietin)
- Insulin receptor (Insulin)
- Eph receptors
- Insulin-like growth factor 1 receptor
- various other growth factor and cytokine receptors
These receptors are relatively rare compared to the much more common types of receptors that cross the cell membrane. An example of a receptor that is a peripheral membrane protein is the elastin receptor.
The ligands for receptors are as diverse as their receptors. Examples include:
|Nicotinic acetylcholine receptor||Acetylcholine, Nicotine||Na+, K+, Ca2+ 17|
|Glycine receptor (GlyR)||Glycine, Strychnine||Cl− > HCO−3 17|
|GABA receptors: GABA-A, GABA-C||GABA||Cl− > HCO−3 17|
|Glutamate receptors: NMDA receptor, AMPA receptor, and Kainate receptor||Glutamate||Na+, K+, Ca2+ 17|
|5-HT3 receptor||Serotonin||Na+, K+ 17|
|P2X receptors||ATP||Ca2+, Na+, Mg2+ 17|
|cyclic nucleotide-gated ion channels||cGMP (vision), cAMP and cGTP (olfaction)||Na+, K+ 17|
|IP3 receptor||IP3||Ca2+ 17|
|Intracellular ATP receptors||ATP (closes channel)17||K+ 17|
|Ryanodine receptor||Ca2+||Ca2+ 17|
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.
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.20
- Ki Database
- Ion channel linked receptors
- Schild regression for ligand receptor inhibition
- Signal transduction
- Stem cell marker
- Wikipedia:MeSH D12.776#MeSH D12.776.543.750 – receptors.2C cell surface
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- 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.
- Stephenson RP (December 1956). "A modification of receptor theory". Br J Pharmacol Chemother 11 (4): 379–93. PMC 1510558. PMID 13383117.
- 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.
- Boulay G, Chrétien L, Richard DE, Guillemette G (November 1994). "Short-term desensitization of the angiotensin II receptor of bovine adrenal glomerulosa cells corresponds to a shift from a high to a low affinity state". Endocrinology 135 (5): 2130–6. doi:10.1210/en.135.5.2130. PMID 7956936.
- Secko D (2011). "Cell surface receptors: a biological conduit for information transfer". The Science Creative Quarterly (6).
- Ben-Shlomo I, Yu Hsu S, Rauch R, Kowalski HW, Hsueh AJ (June 2003). "Signaling receptome: a genomic and evolutionary perspective of plasma membrane receptors involved in signal transduction". Sci. STKE 2003 (187): RE9. doi:10.1126/stke.2003.187.re9. PMID 12815191.
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- Gobeil F, Fortier A, Zhu T, Bossolasco M, Leduc M, Grandbois M, Heveker N, Bkaily G, Chemtob S, Barbaz D (2006). "G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigm". Can. J. Physiol. Pharmacol. 84 (3–4): 287–97. doi:10.1139/y05-127. PMID 16902576.
- Attwood TK, Findlay JB (1994). "Fingerprinting G-protein-coupled receptors". Protein Eng 7 (2): 195–203. doi:10.1093/protein/7.2.195. PMID 8170923.
- Kolakowski LF Jr (1994). "GCRDb: a G-protein-coupled receptor database". Receptors Channels 2 (1): 1–7. PMID 8081729.
- Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ (June 2005). "International Union of Pharmacology. XLVI. G protein-coupled receptor list". Pharmacol. Rev. 57 (2): 279–88. doi:10.1124/pr.57.2.5. PMID 15914470.
- "Search for: gpcr". InterPro. European Bioinformatics Institute. Retrieved 2011-12-27.
- Boulpaep, Emile L.; Walter F., PhD. Boron; Boron, Walter F. (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 90. ISBN 1-4160-2328-3.
- Ronald W. Dudek (1 November 2006). High-yield cell and molecular biology. Lippincott Williams & Wilkins. pp. 19–. ISBN 978-0-7817-6887-0. Retrieved 16 December 2010.
- Alexander SP, Mathie A, Peters JA (February 2007). "Catalytic Receptors". Br. J. Pharmacol. 150 Suppl 1 (S1): S122–7. doi:10.1038/sj.bjp.0707205. PMC 2013840. PMID 17279064.
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- 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)