Receptor (biochemistry)
.svg)
- Ligands, located outside the cell
- Ligands connect to specific receptor proteins based on the shape of the active site of the protein.
- The receptor releases a messenger once the ligand has connected to the receptor.
In
Receptor proteins can be classified by their location.
Receptor proteins can be also classified by the property of the ligands. Such classifications include chemoreceptors, mechanoreceptors, gravitropic receptors, photoreceptors, magnetoreceptors and gasoreceptors.
Structure
The structures of receptors are very diverse and include the following major categories, among others:
- Type 1: GABA; activation of these receptors results in changes in ion movement across a membrane. They have a heteromeric structure in that each subunit consists of the extracellular ligand-binding domain and a transmembrane domain which includes four transmembrane alpha helices. The ligand-binding cavities are located at the interface between the subunits.
- Type 2: G protein-coupled receptors (metabotropic receptors) – 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 helices. The loops connecting the alpha helices form extracellular and intracellular domains. The binding-site for larger peptide ligands is usually located in the extracellular domain whereas the binding site for smaller non-peptide ligands is often located between the seven alpha helices and one extracellular loop.[7] The aforementioned receptors are coupled to different intracellular effector systems via G proteins.[8] G proteins are heterotrimers made up of 3 subunits: α (alpha), β (beta), and γ (gamma). In the inactive state, the three subunits associate together and the α-subunit binds GDP.[9] G protein activation causes a conformational change, which leads to the exchange of GDP for GTP. GTP-binding to the α-subunit causes dissociation of the β- and γ-subunits.[10] Furthermore, the three subunits, α, β, and γ have additional four main classes based on their primary sequence. These include Gs, Gi, Gq and G12.[11]
- 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. The insulin receptor is an example.
- Type 4: Nuclear receptors – While they are called nuclear receptors, they are actually located in the cytoplasm 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 recognizing the DNA sequences specific to this receptor. The N terminus 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.[12]
Membrane receptors may be isolated from cell membranes by complex extraction procedures using
The structures and actions of receptors may be studied by using biophysical methods such as
Binding and activation
Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action in the following equation, for a ligand L and receptor, R. The brackets around chemical species denote their concentrations.
![{\displaystyle {[{\ce {L}}]+[{\ce {R}}]{\ce {<=>[{K_{d}}]}}[{\text{LR}}]}}](https://wikimedia.org/api/rest_v1/media/math/render/svg/8bc59879baab1d42236bb74c50da94e2ceef5afd)
One measure of how well a molecule fits a receptor is its 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 a ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate its receptor.
Agonists versus antagonists
Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist:
- (Full) endogenous ligand with the greatest efficacyfor a given receptor is by definition a full agonist (100% efficacy).
- Partial agonists do not activate receptors with maximal efficacy, even with maximal binding, causing partial responses compared to those of full agonists (efficacy between 0 and 100%).
- covalent bonds (or extremely high affinity non-covalent bonds) with the receptor and completely block it. The proton pump inhibitor omeprazoleis an example of an irreversible antagonist. The effects of irreversible antagonism can only be reversed by synthesis of new receptors.
- Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy).
- benzodiazepines (BZDs) bind to the BZD site on the GABAA receptorand 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.
Constitutive activity
A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity".
The
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
Early forms of the receptor theory of pharmacology stated that a drug's effect is directly proportional to the number of receptors that are occupied.[14] Furthermore, a drug effect ceases as a drug-receptor complex dissociates.
Ariëns & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of ligands bound to receptors.[15][16]
- Affinity: The ability of a drug to combine with a receptor to create a drug-receptor complex.
- Efficacy: The ability of drug to initiate a response after the formation of drug-receptor complex.
Rate
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:[17]
- 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 & slow dissociation
Induced-fit
As a drug approaches a receptor, the receptor alters the conformation of its binding site to produce drug—receptor complex.
Spare Receptors
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.[12]
Receptor regulation
Cells can increase (
- 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-coupled receptors.
- Receptor sequestration (internalization),[18] e.g. in the case of hormone receptors.
Examples and ligands
The ligands for receptors are as diverse as their receptors. GPCRs (7TMs) are a particularly vast family, with at least 810 members. There are also
Ion channels and G protein coupled receptors
Some example ionotropic (LGIC) and metabotropic (specifically, GPCRs) receptors are shown in the table below. The chief neurotransmitters are glutamate and GABA; other neurotransmitters are neuromodulatory. This list is by no means exhaustive.
| Endogenous Ligand | Ion channel receptor (LGIC)
|
G protein coupled receptor (GPCR)
| ||||
|---|---|---|---|---|---|---|
| Receptors | Ion current[nb 2] | Exogenous Ligand | Receptors | G protein | Exogenous Ligand | |
Glutamate
|
Kainate receptors
|
Na+, K+, Ca2+ [19] | Ketamine | mGluRs
|
Gq or Gi/o | - |
GABA
|
GABAA-rho )
|
Cl− > HCO−3 [19] | Benzodiazepines
|
GABAB receptor
|
Gi/o | Baclofen |
| Acetylcholine | nAChR | Na+, K+, Ca2+[19] | Nicotine | mAChR | Gq or Gi
|
Muscarine |
| Glycine | Glycine receptor (GlyR) | Cl− > HCO−3 [19] | Strychnine | - | - | - |
| Serotonin | 5-HT3 receptor
|
Na+, K+ [19] | Cereulide | 5-HT1-2 or 4-7
|
Gs, Gi/o or Gq | - |
| ATP | P2X receptors
|
Ca2+, Na+, Mg2+ [19] | BzATP[citation needed] | P2Y receptors
|
Gs, Gi/o or Gq | - |
| Dopamine | No ion channels[citation needed] | - | - | Dopamine receptor | Gs or Gi/o | - |
Enzyme linked receptors
Enzyme linked receptors include Receptor tyrosine kinases (RTKs), serine/threonine-specific protein kinase, as in bone morphogenetic protein and guanylate cyclase, as in atrial natriuretic factor receptor. Of the RTKs, 20 classes have been identified, with 58 different RTKs as members. Some examples are shown below:
| RTK Class/Receptor Family | Member | Endogenous Ligand | Exogenous Ligand |
|---|---|---|---|
| I | EGFR | EGF | Gefitinib |
| II | Insulin Receptor | Insulin | Chaetochromin |
| IV | VEGFR | VEGF | Lenvatinib |
Intracellular Receptors
Receptors may be classed based on their mechanism or on their position in the cell. 4 examples of intracellular LGIC are shown below:
| Receptor | Ligand | Ion current |
|---|---|---|
cyclic nucleotide-gated ion channels |
olfaction ) |
Na+, K+ [19] |
IP3 receptor |
IP3 |
Ca2+ [19] |
| Intracellular ATP receptors | ATP (closes channel)[19] | K+ [19] |
| Ryanodine receptor | Ca2+ | Ca2+ [19] |
Role in health and disease
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
The main receptors in the
See also
- Ki Database
- Ion channel linked receptors
- Neuropsychopharmacology
- Schild regressionfor ligand receptor inhibition
- Signal transduction
- Stem cell marker
- List of MeSH codes (D12.776)
- Receptor theory
Notes
- ^ In the case of the receptor rhodopsin, the input is a photon, not a chemical
- ions. This is accomplished with selectivity filters, such as the selectivity filter of the K+ ion channel
References
- ^ OCLC 1027900365.
- PMID 15704348.
- ^ ISBN 978-0-8153-4454-4.
- . Retrieved 17 November 2020.
- ISBN 9780071481274.
Nicotine ... is a natural alkaloid of the tobacco plant. Lobeline is a natural alkaloid of Indian tobacco. Both drugs are agonists [of] nicotinic cholinergic receptors ...
- ^ "Curare Drug Information, Professional". Drugs.com. Archived from the original on 16 November 2018. Retrieved 8 December 2020.
- PMID 19912230.
- PMID 21873996.
- ISBN 0697219003.
- ISBN 9781473733602.
- S2CID 24267759.
- ^ ISBN 978-0-7020-3471-8.
- S2CID 2454589.
- PMID 16402126.
- PMID 13229418.
- PMID 13383117.
- ISBN 0-12-643732-7.
- PMID 7956936.
- ^ ISBN 1-4160-2328-3.
- ISBN 978-0-7817-9543-2.
External links
- IUPHAR GPCR Database and Ion Channels Compendium Archived 2019-03-23 at the Wayback Machine
- Human plasma membrane receptome Archived 2019-09-15 at the Wayback Machine
- Cell+surface+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)