Alpha-2 adrenergic receptor

The alpha-2 (α2) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

Effects
The α2-adrenergic receptor binds both norepinephrine released by sympathetic postganglionic fibers and epinephrine (adrenaline) released by the adrenal medulla, binding epinephrine with slightly higher affinity. It has several general functions in common with the α1-adrenergic receptor, but also has specific effects of its own.

General
Common (or still unspecified) effects include:


 * Vasodilation of arteries
 * Vasoconstriction of arteries to heart (coronary artery) however the extent of this effect may be limited and may be negated by the vasodilatory effect from β₂ receptors
 * Vasoconstriction of veins
 * Decrease motility of smooth muscle in gastrointestinal tract
 * Contraction of male genitalia during ejaculation

Individual
Individual actions of the α2 receptor include:


 * Mediates synaptic transmission in pre- and postsynaptic nerve terminals
 * Decrease release of acetylcholine
 * Decrease release of norepinephrine
 * Inhibit norepinephrine system in brain
 * Inhibition of lipolysis in adipose tissue
 * Inhibition of insulin release in pancreas
 * Induction of glucagon release from pancreas
 * platelet aggregation
 * Contraction of sphincters of the gastrointestinal tract
 * ↓ Secretion from salivary gland
 * Relax gastrointestinal tract(presynaptic effect)
 * Decreased aqueous humor fluid production from the ciliary body

Signaling cascade
The alpha subunit of an inhibitory G protein - Gi dissociated from the G protein, and associates with adenyl cyclase (also known as adenylate cyclase or adenylyl cyclase). This causes the inactivation of adenyl cyclase, resulting in a decrease of cAMP produced from ATP. This leads to a decrease of intracellular cAMP. Protein Kinase A is not able to be activated by cAMP, so proteins such as phosphorylase kinase cannot be phosphorylated by PKA. In particular, phosphorylase kinase is responsible for the phosphorylation and activation of glycogen phosphorylase, an enzyme necessary for glycogen breakdown. Thus in this pathway, the downstream effect of adenyl cyclase inactivation is decreased breakdown of glycogen.

The relaxation of gastrointestinal tract motility is by presynaptic inhibition, where transmitters inhibit further release by homotropic effects.

Ligands

 * Agonists
 * Apraclonidine
 * Brimonidine
 * Clonidine
 * Detomidine
 * Dexmedetomidine
 * Guanabenz
 * Guanfacine
 * Lofexidine
 * Medetomidine
 * Romifidine
 * Tizanidine
 * Tolonidine
 * Xylazine
 * Fadolmidine
 * Xylometazoline
 * Oxymetazoline


 * Antagonists
 * Atipamezole
 * Cirazoline
 * Efaroxan
 * Idazoxan
 * Mianserin
 * Mirtazapine
 * Napitane
 * Phenoxybenzamine
 * Phentolamine
 * Rauwolscine
 * Setiptiline
 * Tolazoline
 * Yohimbine

Agonists
Norepinephrine has higher affinity for the α-2 receptor than has epinephrine. Nonselective agonists include the antihypertensive drug clonidine, used to lower blood pressure and hot flashes associated with menopausal symptoms. Clonidine has also been successfully used in indications that exceed what would be expected from a simple blood-pressure lowering drug: it has recently shown positive results in children with ADHD who suffer from tics resulting from the treatment with a CNS stimulant drug, such as Adderall XR or methylphenidate; clonidine also helps alleviate symptoms of opioid withdrawal. The hypotensive effect of clonidine was initially attributed through its agonist action on presynaptic α-2 receptors, which act as a down-regulator on the amount of norepinephrine released in the synaptic cleft, an example of autoreceptor. However, it is now known that clonidine binds to imidazoline receptors with a much greater affinity than α-2 receptors, which would account for its applications outside the field of hypertension alone. Imidazoline receptors occur in the Nucleus Tractus Solitarii and also the Ventrolateral Medulla. Clonidine is now thought to decrease BP via this central mechanism. Other nonselective agonists include dexmedetomidine, lofexidine (another antihypertensive), TDIQ (partial agonist), tizanidine (in spasms, cramping), UK-14,304 and xylazine. Xylazine has veterinary use; in non-human species this is an immobilizing and anesthetic drug, presumptively also mediated by α-2 adrenergic receptors because it is reversed by yohimbine, an α-2 antagonist.

α2A selective agonists include guanfacine (an antihypertensive) and octopamine, which is also a β3 agonist.

(R)-3-Nitrobiphenyline is an α2C selective agonist.

Antagonists
Nonselective alpha blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan* (experimental), mirtazapine (a tetracyclic antidepressant), mianserin (a tetracyclic antidepressant), SB-269,970 and yohimbine* (a purported aphrodisiac).

α2A selective alpha blockers include BRL-44408 and RX-821,002, while α2B selective alpha blockers include ARC-239 and imiloxan.

α2C selective alpha blockers include JP-1302 and spiroxatrine, the latter also being a serotonin 5-HT1A antagonist.