Receptor (biochemistry)

In the field of biochemistry, a receptor is a molecule most often found on the surface of a cell, which receives chemical signals originating externally from the cell. Through binding to a receptor, these signals direct a cell to do something—for example to divide or die, or to allow certain molecules to enter or exit.

Receptors are protein molecules, embedded in either the plasma membrane (cell surface receptors) or the cytoplasm or nucleus (nuclear receptors) of a cell, to which one or more specific kinds of signaling molecules may attach. A molecule which binds (attaches) to a receptor is called a ligand, and may be a peptide (short protein) or other small molecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin.

Numerous receptor types are found within a typical cell and each type is linked to a specific biochemical pathway. Furthermore each type of receptor recognizes and binds only certain ligand shapes (in analogy to a lock and key where the lock represents the receptor and the key, its ligand). Hence the selective binding of specific a ligand to its receptor activates on inhibits a specific biochemical pathway.

Ligand binding stabilizes a certain receptor conformation (the three-dimensional shape of the receptor protein). This is often associated with gain of or loss of protein activity, ordinarily leading to some sort of cellular response. However, some ligands (e.g. antagonists) merely block receptors without inducing any response. Ligand-induced changes in receptors result in cellular changes which constitute the biological activity of the ligands.

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 located at the interface between the subunits.
  • receptor tyrosine kinase – Functional receptors are homodimers. Each monomer possess a single transmembrane alpha helix and a extracellular domain containing the ligand binding cavity and an intracellular domain with catalytic activity.
• soluble globular proteins
  • nuclear receptors – Composed of a C-terminal DNA-binding domain (DBD) and a N-terminal ligand-binding domain (LDB). The LBD is composed of twelve alpha helices and an antiparallel beta sheet. The ligand binding cavity is buried within the interior of the LBD.^[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 has 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.

(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 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.

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.

Ariens & Stephenson

Ariens & 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

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 rate of dissociation & association not number of receptors occupied:

• 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.

• Receptor desensitization^[7]
• Uncoupling of receptor effector molecules.
• Receptor sequestration (internalization).^[7]

Types

Transmembrane

Transmembrane receptors can be classified into three families based on the way they transmit information into the interior of the cell:^[8]

• G protein-linked
• Ion channel-linked
• Enzyme-linked

The entire repertoire of human plasma membrane receptors is listed at the Human Plasma Membrane Receptome.^[9][10]

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.^[11] 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:^{[12][13][14][15]}

• Class A (or 1) (Rhodopsin-like)
• Class B (or 2) (Secretin receptor family)
• Class C (or 3) (Metabotropic glutamate/pheromone)
• Class D (or 4) (Fungal mating pheromone receptors)
• Class E (or 5) (Cyclic AMP receptors)
• Class F (or 6) (Frizzled/Smoothened)

Ion channel-linked

Ligand gated ion channels also known as ionotropic receptors are heteromeric or homomeric oligomers.^[16] 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.^[17][18]

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;

• Erythropoietin receptor (Erythropoietin)
• Insulin receptor (Insulin)
• Eph receptors
• Insulin-like growth factor 1 receptor
• various other growth factor and cytokine receptors

Miscellaneous

• sigma1 (neurosteroids)

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

• nuclear receptor:
  • Steroid hormone receptor

Ligands

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

Extracellular

Intracellular

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

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.^[19]

See also

• K_i 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

References

External links

• IUPHAR GPCR Database and Ion Channels Compendium
• Human plasma membrane receptome
• MeSH Cell+surface+receptors