恒常的活性、構成的活性

WordNet

any specific behavior; "they avoided all recreational activity"
(chemistry) the capacity of a substance to take part in a chemical reaction; "catalytic activity"

PrepTutorEJDIC

〈U〉『活動』,働き;活力 / 《しばしば複数形で》(種々の)『活動』,行事;(学生の)学内(外)活動,クラブ活動 / 〈U〉(商況・市場などの)活発,活気
=constituent1

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/18 01:05:33」(JST)

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1. Ligands
2. Receptors
3. Secondary Messengers

These are examples of membrane receptors.

In biochemistry and pharmacology, a receptor is a protein molecule usually found embedded within the plasma membrane surface of a cell that receives chemical signals from outside the 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 the cell. In this sense, a receptor is a protein molecule that recognises and responds to endogenous chemical signals, e.g. the 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 the cell's plasma 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.

1 Structure
2 Binding and activation
- 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
- 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 fast neurotransmitters such as acetylcholine (nicotinic) and GABA and activation of these receptor results in changes in ion movement across the 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 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 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] These receptors are coupled to different intracellular effector systems via G-proteins.^[2]
Type 3: kinase linked and related receptors (see "Receptor tyrosine kinase", and "Enzyme-linked receptor") - These receptors 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, these 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.^[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 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.

Affinity is a measure of the tendency of the ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate the receptor.

Agonists versus antagonists

Efficacy spectrum of receptor ligands.

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 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 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 agonists reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy).
Allosteric modulators: These 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 idea of receptor agonism and antagonism only refers to interaction between receptors and ligands and not their biological effects.

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 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).

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.

Ariëns & 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

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 the drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, not number of receptors occupied:^[7]

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.

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 the system has spare receptors or 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 its sensitivity to this 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	Ligand	Ion current
Nicotinic acetylcholine receptor	Acetylcholine, Nicotine	Na⁺, K⁺, Ca²⁺^[9]
Glycine receptor (GlyR)	Glycine, Strychnine	Cl⁻ > HCO⁻₃ ^[9]
GABA receptors: GABA-A, GABA-C	GABA	Cl⁻ > HCO⁻₃ ^[9]
Glutamate receptors: NMDA receptor, AMPA receptor, and Kainate receptor	Glutamate	Na⁺, K⁺, Ca²⁺ ^[9]
5-HT₃ receptor	Serotonin	Na⁺, K⁺ ^[9]
P2X receptors	ATP	Ca²⁺, Na⁺, Mg²⁺ ^[9]

Intracellular

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

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]

References

^ Congreve M, Marshall F (March 2010). "The impact of GPCR structures on pharmacology and structure-based drug design". Br. J. Pharmacol. 159 (5): 986–96. doi:10.1111/j.1476-5381.2009.00476.x. PMC 2839258. PMID 19912230.
^ Kou Qin, Chunmin Dong, Guangyu Wu & Nevin A Lambert (August 2011). "Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers". Nature Chemical Biology 7 (11): 740–747. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
^ ^a ^b Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G (2012). Rang & Dale's Pharmacology (7th ed.). Elsevier Churchill Livingstone. ISBN 978-0-7020-3471-8.
^ Milligan G (December 2003). "Constitutive activity and inverse agonists of G protein-coupled receptors: a current perspective". Mol. Pharmacol. 64 (6): 1271–6. doi:10.1124/mol.64.6.1271. PMID 14645655.
^ Ariens EJ (September 1954). "Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory". Arch Int Pharmacodyn Ther 99 (1): 32–49. PMID 13229418.
^ Stephenson RP (December 1956). "A modification of receptor theory". Br J Pharmacol Chemother 11 (4): 379–93. doi:10.1111/j.1476-5381.1956.tb00006.x. PMC 1510558. PMID 13383117.
^ Silverman RB (2004). "3.2.C Theories for Drug—Receptor Interactions". The Organic Chemistry of Drug Design and Drug Action (2nd ed.). Amsterdam: Elsevier Academic Press. ISBN 0-12-643732-7.
^ Boulay G, Chrétien L, Richard DE, Guillemette G (November 1994). "Short-term desensitization of the angiotensin II receptor of bovinde adrenal glomerulosa cells corresponds to a shift from a high to low affinity state". Endocrinology 135 (5): 2130–6. doi:10.1210/en.135.5.2130. |accessdate= requires |url= (help)
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Boulpaep, EL; Boron WF (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 90. ISBN 1-4160-2328-3.
^ Waltenbaugh C, Doan T, Melvold R, Viselli S (2008). Immunology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 20. ISBN 0-7817-9543-5.

External links

IUPHAR GPCR Database and Ion Channels Compendium
Human plasma membrane receptome
Cell surface receptors at the US National Library of Medicine Medical Subject Headings (MeSH)

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