![Receptor (Biochemistry)](https://upload.wikimedia.org/wikipedia/commons/0/0e/Receptor_%28Biochemistry%29.svg)
In
biochemistry
Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
and
pharmacology, receptors are chemical structures, composed of
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, that receive and
transduce signals that may be integrated into biological systems.
These signals are typically chemical messengers which bind to a receptor and cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration.
Relaying sends the signal onward, amplification increases the effect of a single
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
, and integration allows the signal to be incorporated into another biochemical pathway.
Receptor proteins can be classified by their location. Transmembrane receptors include
ligand-gated ion channel
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
s,
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, and enzyme-linked
hormone receptor
A hormone receptor is a receptor molecule that binds to a specific chemical messenger . Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other recepto ...
s.
Intracellular receptors are those found inside the cell, and include cytoplasmic receptors and
nuclear receptors.
A molecule that binds to a receptor is called a
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
and can be a protein,
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
(short protein), or another
small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...
, such as a
neurotransmitter,
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
, pharmaceutical drug, toxin,
calcium ion
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
or parts of the outside of a virus or microbe. An endogenously produced substance that binds to a particular receptor is referred to as its endogenous ligand. E.g. the endogenous ligand for the
nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...
is
acetylcholine, but it can also be activated by
nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
and blocked by
curare
Curare ( /kʊˈrɑːri/ or /kjʊˈrɑːri/; ''koo-rah-ree'' or ''kyoo-rah-ree'') is a common name for various alkaloid arrow poisons originating from plant extracts. Used as a paralyzing agent by indigenous peoples in Central and South ...
. Receptors of a particular type are linked to specific cellular biochemical pathways that correspond to the signal. While numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure. This has been analogously compared to
how locks will only accept specifically shaped keys. When a ligand binds to a corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway, which may also be highly specialised.
Structure
![Transmembrane receptor](https://upload.wikimedia.org/wikipedia/commons/4/48/Transmembrane_receptor.svg)
The structures of receptors are very diverse and include the following major categories, among others:
* Type 1:
Ligand-gated ion channel
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
s (ionotropic receptors) – These receptors are typically the targets of fast neurotransmitters such as acetylcholine (nicotinic) and
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 alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
. The ligand-binding cavities are located at the interface between the subunits.
* Type 2:
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s (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.
The aforementioned receptors are coupled to different intracellular effector systems via
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their a ...
s.
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. 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. Furthermore, the three subunits, α, β, and γ have additional four main classes based on their primary sequence. These include G
s, G
i, G
q and G
12.
* Type 3: Kinase-linked and related receptors (see "
Receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...
" and "
Enzyme-linked receptor An enzyme-linked receptor, also known as a catalytic receptor, is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protei ...
") – 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
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose ho ...
is an example.
* Type 4:
Nuclear receptors – While they are called nuclear receptors, they are actually located in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
and migrate to the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
* Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
after binding with their ligands. They are composed of a
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
ligand-binding region, a core
DNA-binding domain
A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...
(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.
Membrane receptors may be isolated from cell membranes by complex extraction procedures using
solvents,
detergents, and/or
affinity purification
Affinity chromatography is a method of separating a biomolecule from a mixture, based on a highly specific macromolecular binding interaction between the biomolecule and another substance. The specific type of binding interaction depends on the ...
.
The structures and actions of receptors may be studied by using biophysical methods such as
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
,
NMR
Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with ...
,
circular dichroism, and
dual polarisation interferometry
Dual-polarization interferometry (DPI) is an analytical technique that probes molecular layers adsorbed to the surface of a waveguide using the evanescent wave of a laser beam. It is used to measure the conformational change in proteins, or othe ...
.
Computer simulations of the dynamic behavior of receptors have been used to gain understanding of their mechanisms 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
In chemistry, the law of mass action is the proposition that the rate of the chemical reaction is directly proportional to the product of the activities or concentrations of the reactants. It explains and predicts behaviors of solutions in dy ...
in the following equation, for a ligand L and receptor, R. The brackets around chemical species denote their concentrations.
:
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
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
, 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
![Efficacy spectrum](https://upload.wikimedia.org/wikipedia/commons/b/bd/Efficacy_spectrum.png)
Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist:
* ''(Full)
agonists'' are able to activate the receptor and result in a strong biological response. The natural
endogenous ligand with the greatest
efficacy for a given receptor is by definition a full agonist (100% efficacy).
* ''
Partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...
s'' 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%).
*
''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
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
(or extremely high affinity non-covalent bonds) with the receptor and completely block it. The proton pump inhibitor
omeprazole
Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upp ...
is 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).
* ''
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. For example,
benzodiazepines (BZDs) bind to the BZD site on the
GABAA 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.
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 constitutive activity of a receptor may be blocked by an
inverse agonist. The anti-obesity drugs
rimonabant
Rimonabant (also known as SR141716; trade names Acomplia, Zimulti) is an anorectic antiobesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in t ...
and
taranabant
Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 (CB1) inverse agonist that was investigated as a potential treatment for obesity due to its anorectic effects. It was discovered by Merck & Co.
In October 2008, Merck has stopped ...
are inverse agonists at the cannabinoid
CB1 receptor
Cannabinoid receptor type 1 (CB1), also known as cannabinoid receptor 1, is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. The human CB1 receptor is expressed in the peripheral nervous system and centr ...
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.
The
GABAA receptor has constitutive activity and conducts some basal current in the absence of an agonist. This allows
beta carboline
β-Carboline (9''H''- pyrido ,4-''b'' ndole) represents the basic chemical structure for more than one hundred alkaloids and synthetic compounds. The effects of these substances depend on their respective substituent. Natural β-carbolines prima ...
to act as an inverse agonist and reduce the current ''below'' basal levels.
Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as
precocious puberty
In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...
(due to mutations in luteinizing hormone receptors) and
hyperthyroidism
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidis ...
(due to mutations in thyroid-stimulating hormone receptors).
Theories of drug-receptor interaction
Occupation
Early forms of the
receptor theory
Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that ...
of pharmacology stated that a drug's effect is directly proportional to the number of receptors that are occupied. 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.
*
Affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
: 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:
* 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.
Receptor regulation
Cells can increase (
upregulate
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pro ...
) or decrease (
downregulate
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...
) the number of receptors to a given
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
or
neurotransmitter to alter their sensitivity to different molecules. This is a locally acting
feedback mechanism.
* 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),
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
LGIC
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
s for at least a dozen endogenous ligands, and many more receptors possible through different subunit compositions. Some common examples of ligands and receptors include:
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
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second ...
. This list is by no means exhaustive.
Enzyme linked receptors
Enzyme linked receptors include
Receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...
s (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:
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:
Role in health and disease
In genetic disorders
Many
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
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
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...
are
pattern recognition receptors
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
(PRRs),
toll-like receptor
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize ...
s (TLRs),
killer activated and
killer inhibitor receptor
Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map in ...
s (KARs and KIRs),
complement receptor
A complement receptor is a membrane-bound receptor belonging to the complement system, which is part of the innate immune system. Complement receptors bind effector protein fragments that are produced in response to antigen-antibody complexes or ...
s,
Fc receptors,
B cell receptor
The B cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, ...
s and
T cell receptor
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding ...
s.
See also
*
Ki Database
*
Ion channel linked receptors
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
*
Neuropsychopharmacology
Neuropsychopharmacology, an interdisciplinary science related to psychopharmacology (study of effects of drugs on the mind) and fundamental neuroscience, is the study of the neural mechanisms that drugs act upon to influence behavior. It entails ...
*
Schild regression
In pharmacology, Schild regression analysis, named for Heinz Otto Schild, is a tool for studying the effects of agonists and antagonists on the response caused by the receptor or on ligand-receptor binding.
Dose-response curves can be cons ...
for ligand receptor inhibition
*
Signal transduction
*
Stem cell marker Stem cell markers are genes and their protein products used by scientists to isolate and identify stem cells. Stem cells can also be identified by functional assays. Below is a list of genes/protein products that can be used to identify various typ ...
*
List of MeSH codes (D12.776)
The following is a partial list of the "D" codes for Medical Subject Headings (MeSH), as defined by the United States National Library of Medicine (NLM).
This list continues the information at List of MeSH codes (D12.644). Codes following these ...
*
Receptor theory
Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that ...
Notes
References
External links
IUPHAR GPCR Database and Ion Channels CompendiumHuman plasma membrane receptome*
{{genarch
Cell biology
Cell signaling
Membrane biology