Receptor (biochemistry).html



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In biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling (or "signal") molecule may attach. A molecule which binds to a receptor is called a "ligand," and may be a peptide (such as a neurotransmitter), a hormone, a pharmaceutical drug, or a toxin, and when such binding occurs, the receptor undergoes a conformational change which ordinarily initiates a cellular response. However, some ligands merely block receptors without inducing any response (e.g. antagonists). Ligand-induced changes in receptors result in physiological changes which constitute the biological activity of the ligands.

Overview

The shapes and actions of receptors are studied by X-ray crystallography and computer modelling, which have advanced the understanding of drug action at the binding sites of receptors.

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

Depending on their functions and ligands, several types of receptors may be identified:

• Some receptor proteins are peripheral membrane proteins.
• Many hormone and neurotransmitter receptors are transmembrane proteins: transmembrane receptors are embedded in the phospholipid bilayer of cell membranes, that allow the activation of signal transduction pathways in response to the activation by the binding molecule, or ligand.
  • Metabotropic receptors are coupled to G proteins and affect the cell indirectly through enzymes which control ion channels.
  • Ionotropic receptors contain a central pore which functions as a ligand-gated ion channel.
• Another major class of receptors are intracellular proteins such as those for steroid and intracrine peptide hormone receptors. These receptors often can enter the cell nucleus and modulate gene expression in response to the activation by the ligand.

Binding and activation

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 the 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 or muscle contraction), is only achieved after a significant number of receptors are activated.

If the receptor exists in two states (see this picture), then the ligand binding must account for these two receptor states. For a more detailed discussion of two-state binding, which is thought to occur as an activation mechanism in many receptors see this link.

Constitutive activity

A receptor which is capable of producing its biological response in the absence of a bound ligand is said to display "constitutive activity." ^[1] 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). Psychostimulants act as inverse agonists on dopamine receptors.

For the use of statistical mechanics in a quantitative study of the ligand-receptor binding affinity, see the comprehensive article^[2] on the configuration integral.

Agonists versus antagonists

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. Most natural ligands are full agonists.
• Partial agonists do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists.
• Antagonists bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of other agonists.
• Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity.

Peripheral membrane protein receptors

See also: Peripheral membrane protein

Transmembrane receptors

Main article: Transmembrane receptor

Metabotropic receptors

Main article: Metabotropic receptor

G protein-coupled receptors

Main article: G protein-coupled receptor

These receptors are also known as seven transmembrane receptors or 7TM receptors, because they pass through the membrane seven times.

• Muscarinic acetylcholine receptor (Acetylcholine and Muscarine)
• Adenosine receptors (Adenosine)
• Adrenoceptors (also known as Adrenergic receptors, for adrenaline, and other structurally related hormones and drugs)
• GABA receptors, Type-B (γ-Aminobutyric acid or GABA)
• Angiotensin receptors (Angiotensin)
• Cannabinoid receptors (Cannabinoids)
• Cholecystokinin receptors (Cholecystokinin)
• Dopamine receptors (Dopamine)
• Glucagon receptors (Glucagon)
• Metabotropic glutamate receptors (Glutamate)
• Histamine receptors (Histamine)
• Olfactory receptors (for the sense of smell)
• Opioid receptors (Opioids)
• Rhodopsin (a photoreceptor)
• Secretin receptors (Secretin)
• Serotonin receptors, except Type-3 (Serotonin, also known as 5-Hydroxytryptamine or 5-HT)
• Somatostatin receptors (Somatostatin)
• Calcium-sensing receptor (Calcium)
• Chemokine receptors (Chemokines)
• many more ...

Please help improve this section by expanding it. Further information might be found on the talk page or at requests for expansion. (June 2008)

Receptor tyrosine kinases

Main article: Receptor tyrosine kinase

These receptors detect ligands 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
• ....

Guanylyl cyclase receptors

• GC-A & GC-B: receptors for Atrial-natriuretic peptide (ANP) and other natriuretic peptides
• GC-C: Guanylin receptor

Ionotropic receptors

Ionotropic receptors are heteromeric or homomeric oligomers ^[3]. They are receptors that respond to extracellular ligands and receptors that respond to intracellular ligands.

Extracellular ligands

Intracellular ligands

The entire repertoire of human plasma membrane receptors is listed at the Human Plasma Membrane Receptome (http://www.receptome.org).

Intracellular receptors

Main article: Intracellular receptor

Transcription factors

• nuclear receptor:
  • Steroid hormone receptor

Various

• Ionotropic receptors (IP₃ receptor above)
• sigma1 (neurosteroids)
• G protein-coupled receptors ^[4]

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.

Receptor Regulation

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 desensitization

Ligand-bound desensitation of receptors was first characterized by Katz and Thesleff in the nicotine acetylcholine receptor^[5][6] Prolonged or repeated exposure to a stimulus often results in decreased responsiveness of that receptor for a stimulus. Receptor desensitization results in altered affinity for the ligand.^[5] Receptor desensitization can modeled by a two-state model that also predicts that antagonists combined with agonists can prevent receptor desensitization ^[7] See this link [1] for detailed molecular description

Desensitation may be accomplished by

• Receptor phosphorylation.^[8]
• Uncoupling of receptor effector molecules.
• Receptor sequestration (internalization).^[8]

In immune system

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. ^[9]

See also

• Signal transduction
• Neuropsychopharmacology
• Schild regression for ligand receptor inhibition
• K_i Database
• Wikipedia:MeSH D12.776#MeSH D12.776.543.750 --- receptors.2C cell surface

References

1. ^ 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. 
2. ^ Vu-Quoc, L., Configuration integral (statistical mechanics), 2008.
3. ^ ^{a b c d e f g h i j k l} Medical Physiology, Boron & Boulpaep, ISBN 1-4160-2328-3, Elsevier Saunders 2005. Updated edition. Page 90.
4. ^ Gobeil F, et al. (2006) G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigm. Can J Physiol Pharmacol. 2006 Mar-Apr;84(3-4):287-97. PMID 16902576
5. ^ ^{a b} Y. Sun, R. Olson, M. Horning, N. Armstrong, M. Mayer and E. Gouaux. (2002) Mechanism of glutamate receptor desensitization Nature 417, 245-253
6. ^ S. Pitchford, J.W. Day, A. Gordon and D. Mochly-Rosen. (1992) Acetylcholine receptor desensitization is Regulate by activation-induced extracellular adenosine accumulation. The Journal of Neuroscience, 1.311): 4540-4544.
7. ^ Lanzara, "Optimal Agonist/Antagonist Combinations Maintain Receptor Response by Preventing Rapid Beta-1 adrenergic Receptor Desensitization" Intl. J. Pharmacol., 1(2): 122-131, 2005.http://www.bio-balance.com/ijp.pdf
8. ^ ^{a b} G. Boulay, L. Chrbtien, D.E. Richard, AND G. Guillemettes. (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 Vol. 135. No. 5 2130-2136
9. ^ Lippincott's Illustrated Reviews: Immunology. Paperback: 384 pages. Publisher: Lippincott Williams & Wilkins; (July 1, 2007). Language: English. ISBN-10: 0781795435. ISBN-13: 978-0781795432. Page 20

External links

• IUPHAR GPCR Database and Ion Channels Compendium
• MeSH Cell+surface+receptors