MarketAlpha-2 adrenergic receptor
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Alpha-2 adrenergic receptor

The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three homologous subtypes, 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.

Cellular localization
The α2A adrenergic receptor is localised in the following central nervous system (CNS) structures: • Brainstem (especially the locus coeruleus as presynaptic & somatodendritic autoreceptor ) • MidbrainHypothalamus • Olfactory system • HippocampusSpinal cordCerebral cortexCerebellumSeptum Whereas the α2B adrenergic receptor is localised in the following CNS structures: • Thalamus • Pyramidal layer of the hippocampus • Cerebellar Purkinje layer and the α2C adrenergic receptor is localised in the CNS structures: • Midbrain • Thalamus • AmygdalaDorsal root ganglia • Olfactory system • HippocampusCerebral cortexBasal gangliaSubstantia nigraVentral tegmentum == Effects ==
Effects
The α2-adrenergic receptor is classically located on vascular prejunctional terminals where it inhibits the release of norepinephrine (noradrenaline) in a form of negative feedback. It is also located on the vascular smooth muscle cells of certain blood vessels, such as those found in skin arterioles or on veins, where it sits alongside the more plentiful α1-adrenergic receptor. It has several general functions in common with the α1-adrenergic receptor, but also has specific effects of its own. Agonists (activators) of the α2-adrenergic receptor are frequently used in anaesthesia where they affect sedation, muscle relaxation and analgesia through effects on the central nervous system (CNS). In the brain, α2-adrenergic receptors can be localized either pre- or post-synaptically, however the majority of receptors appear to be post-synaptic. For example, the α2A adrenergic receptor subtype is post-synaptic in the prefrontal cortex, where these receptors strengthen cognitive and executive functions by inhibiting cAMP opening of potassium channels, thus enhancing prefrontal connections and neuronal firing. The α2A-adrenergic agonist, guanfacine, is now used to treat prefrontal cortical cognitive disorders such as attention deficit hyperactivity disorder (ADHD). General Common effects include: • Suppression of release of norepinephrine (noradrenaline) by negative feedback • 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 • Constriction of some vascular smooth muscle • Venoconstriction of veins • Decrease motility of smooth muscle in gastrointestinal tract • Inhibition of lipolysis • Sedation of lipolysis in adipose tissue • Induction of glucagon release from pancreas • platelet aggregation • Contraction of sphincters of the gastrointestinal tract • Decreased secretion from salivary gland • Relax gastrointestinal tract (presynaptic effect) • Decreased aqueous humor fluid production from the ciliary body == Signaling cascade ==
Signaling cascade
The α subunit of an inhibitory G protein - Gi dissociates from the G protein, and associates with adenylyl cyclase. This causes the inactivation of adenylyl cyclase, resulting in a decrease of cAMP produced from ATP, which leads to a decrease of intracellular cAMP. PKA 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 adenylyl 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==
Ligands
Agonists4-NEMD7-Me-marsanidine (also I1 agonist) • Agmatine (also I agonist, NMDA, 5-HT3, nicotinic antagonist and NOS inhibitor) • ApraclonidineBrimonidineCannabigerol (also acts as a moderate affinity 5-HT1A receptor antagonist, and low affinity CB1 receptor antagonist). • Clonidine (also I1 agonist) • DetomidineDexmedetomidineFadolmidineGuanabenzGuanfacineLofexidineMarsanidineMedetomidineMethyldopaMivazerolOxymetazoline (also α1 agonist) • TiamenidineTizanidineTolonidineXylazineXylometazoline Norepinephrine has higher affinity for the α2 receptor than epinephrine does, and therefore relates less to the latter's functions. clonidine also helps alleviate symptoms of opioid withdrawal. The hypotensive effect of clonidine was initially attributed through its agonist action on presynaptic α2 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 α2 receptors, which would account for its applications outside the field of hypertension alone. Imidazoline receptors occur in the nucleus tractus solitarii and also the centrolateral medulla. Clonidine is now thought to decrease blood pressure via this central mechanism. Other nonselective agonists include dexmedetomidine, lofexidine (another antihypertensive), TDIQ (partial agonist), tizanidine (in spasms, cramping) and xylazine. Xylazine has veterinary use. In the European Union, dexmedetomidine received a marketing authorization from the European Medicines Agency (EMA) on August 10, 2012, under the brand name of Dexdor. It is indicated for sedation in the ICU for patients needing mechanical ventilation. In non-human species this is an immobilizing and anesthetic drug, presumptively also mediated by α2 adrenergic receptors because it is reversed by yohimbine, an α2 antagonist. α2A selective agonists include guanfacine (an antihypertensive) and brimonidine (UK 14,304). (R)-3-nitrobiphenyline is an α2C selective agonist as well as being a weak antagonist at the α and α subtypes. Antagonists1-PP (active metabolite of buspirone and gepirone) • AripiprazoleAsenapineAtipamezoleCirazolineClozapineEfaroxanFipamezoleIdazoxanLurasidoneMelperoneMianserinMirtazapineNapitaneOlanzapinePaliperidone (also primary active metabolite of risperidone) • PhenoxybenzaminePhentolaminePiribedilRauwolscineRisperidoneRotigotine (α2B antagonist, non-selective) • QuetiapineNorquetiapine (primary active metabolite of quetiapine) • SetiptilineTolazolineYohimbineZiprasidoneZotepine (discontinued) Non-selective α blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan and SB-269,970. Yohimbine is a relatively selective α2 blocker that has been investigated as a treatment for erectile dysfunction. Tetracyclic antidepressants mirtazapine and mianserin are also potent α antagonists with mirtazapine being more selective for α2 subtype (~30-fold selective over α1) than mianserin (~17-fold). α2A selective blockers include BRL-44408 and RX-821,002. α2B selective blockers include ARC-239 and imiloxan. α2C selective blockers include JP-1302 and spiroxatrine, the latter also being a serotonin 5-HT1A antagonist. == See also ==
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