Receptor (biochemistry)

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(Redirected from Receptor protein)
For other uses, see Receptor (disambiguation).

1. Ligands
2. Receptors
3. Secondary Messengers
These are examples of membrane receptors.
In biochemistry and pharmacology, a receptor is a protein-molecule that receives chemicalsignals 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-proteins are embedded in all cells' plasmatic-membranes; facing extracellular-(cell
surface receptors), cytoplasmic (cytoplasmic-receptors), or in the nucleus (nuclear receptors).
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.

Contents

1 Structure

2 Binding and activation

o

2.1 Agonists versus antagonists

2.2 Constitutive-activity

2.3 Theories of drug-receptor interaction

2.3.1 Occupation-theory

2.3.2 Rate-theory

2.3.3 Induced-fit theory

2.3.4 Spare-receptors

3 Receptor-regulation

4 Ligands
o

4.1 Extracellular

4.2 Intracellular

5 Role in genetic disorders

6 In the immune system

7 See also

8 References

9 External links

Structure

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

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 fastneurotransmitters such as acetylcholine (nicotinic) and GABA; and, activation of these
receptors results in changes in ion-movement across a membrane. They have a heterostructure. 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 receptors (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 transmembranealpha 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] The
aforementioned receptors are coupled to different intracellular-effector systems via Gproteins.[2]

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 receptors 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 DNAsequences specific to this receptor. The N-terminal interacts with other cellulartranscription factors in a ligand-independent manner; and, depending on these
interactions it can modify the binding/activity of the receptor. Steroid and thyroidhormone receptors are examples of such receptors.[3]

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 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.
(the brackets stand for concentrations
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

Efficacy spectrum of receptor ligands.

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 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 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 receptorblockade, 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-agonists reduce the activity of receptors by inhibiting their constitutiveactivity (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.

Constitutive-activity
A receptor which is capable of producing a biological-response in the absence of a boundligand is said to display "constitutive-activity".[4] 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 inheriteddiseases, 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 a drug-effect is directly proportional to
the number of receptors that are occupied. Furthermore, a drug effect ceases as a drugreceptor complex dissociates.
Arins & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of
ligands bound to receptors.[5][6]

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.

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 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:[7]

Agonist: A drug with a fast association and a fast dissociation.

Partial-agonist: A drug with an intermediate-association and an intermediatedissociation.

Antagonist: A drug with a fast-association & slow-dissociation

Induced-fit theory
As a drug approaches a receptor, the receptor alters the conformation of its binding-site to
produce drugreceptor 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.[3]

Receptor-regulation

Cells can increase (upregulate) or decrease (downregulate) the number of receptors to a given
hormone or neurotransmitter to alter their sensitivity to different molecule. 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 couple receptor.

Receptor sequestration (internalization).[8] e.g. in the case of hormone receptors.

Ligands
The ligands for receptors are as diverse as their receptors. Examples include:[9]

Extracellular
Receptor
Nicotinic acetylcholine receptor

Ligand
Acetylcholine,
Nicotine
Glycine, Strychnine
GABA

Glycine receptor (GlyR)

GABA receptors: GABA-A, GABA-C
Glutamate receptors: NMDA receptor, AMPA receptor,
Glutamate
and Kainate receptor
5-HT3 receptor
Serotonin
P2X receptors

ATP

Ion current
Na+, K+, Ca2+[9]
Cl > HCO3 [9]
Cl > HCO3 [9]
Na+, K+, Ca2+ [9]
Na+, K+ [9]
Ca2+, Na+, Mg2+
[9]

Intracellular
Receptor

Ligand
cGMP (vision), cAMP and cGTP
cyclic nucleotide-gated ion channels
(olfaction)
IP3 receptor
IP3
Intracellular ATP receptors
ATP (closes channel)[9]
Ryanodine receptor
Ca2+

Ion current
Na+, K+ [9]
Ca2+ [9]
K+ [9]
Ca2+ [9]

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.[10]

See also

Ki Database

Ion channel linked receptors

Neuropsychopharmacology

Schild regression for ligand receptor inhibition

Signal transduction

Stem cell marker

Wikipedia:MeSH D12.776#MeSH D12.776.543.750 receptors.2C cell surface