Constitutive activity

For other uses, see Receptor (disambiguation).

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.

Structure

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

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

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.

The receptor-ligand affinity is greater than enzyme-substrate affinity. 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.

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. 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).

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".[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).

Theories of drug receptor interaction

Occupation theory

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

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

  • 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

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 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

Induced fit theory

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

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.

Types

Transmembrane

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
  • Enzyme-linked

Other transmembrane receptors include sigma receptors.

The entire repertoire of human plasma membrane receptors is listed at the Human Plasma Membrane Receptome.[10][11]

G protein-linked

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.

The GPCRs can be grouped into 6 classes based on sequence homology and functional similarity:[13][14][15][16]

Ion channel-linked

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.

Enzyme-linked

An enzyme-linked receptor also known as a catalytic receptor is a transmembrane receptor, where the binding of an extracellular ligand triggers enzymatic activity on the intracellular side.[18][19]

Tyrosine kinases

These receptors detect ligands through their extracellular domain and propagate signals via the tyrosine kinase of their intracellular domains. This family of receptors includes;

Other

Sigma receptors:

Peripheral membrane

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.

Intracellular

Transcription factors

Ligands

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

Extracellular

Receptor Ligand Ion current
Nicotinic acetylcholine receptor Acetylcholine, Nicotine Na+, K+, Ca2+ [17]
Glycine receptor (GlyR) Glycine, Strychnine Cl > HCO3 [17]
GABA receptors: GABA-A, GABA-C GABA Cl > HCO3 [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]

Intracellular

Receptor Ligand Ion current
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]

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

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.[20]

See also

References

External links

  • IUPHAR GPCR Database and Ion Channels Compendium
  • Human plasma membrane receptome
  • Medical Subject Headings (MeSH)

This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.