Other uses|Receptor (disambiguation)
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-protein+s are embedded in all cells' plasmatic-membranes; facing extracellular-(cell surface receptor+s), cytoplasmic (cytoplasmic-receptors), or in the nucleus+ (nuclear receptor+s). 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.
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 receptor+s (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 helix|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. The aforementioned receptors are coupled to different intracellular-effector systems via G-proteins.
* 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 receptor+s – 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.
One measure of how well a molecule fits a receptor is its 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+, 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.
Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist:
* ''(Full) agonist+s'' 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 agonist+s'' 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-agonist+s'' 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.
A receptor which is capable of producing a biological-response in the absence of a bound-ligand is said to display "constitutive-activity". 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).
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+ and Stephenson introduced the terms "affinity" and "efficacy" to describe the action of ligands bound to receptors.
* 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.
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:
* 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 and slow-dissociation
As a drug approaches a receptor, the receptor alters the conformation of its binding-site to produce drug—receptor complex.
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.
* 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). e.g. in the case of hormone receptors.
The ligands for receptors are as diverse as their receptors. Examples include:
Many genetic disorder+s 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.