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.[1] Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

See also: Adrenergic receptor

Cellular localization

The α2A adrenergic receptor is localised in the following central nervous system (CNS) structures:[2]

Whereas the α2B adrenergic receptor is localised in the following CNS structures:[2]

  • Olfactory system
  • Thalamus
  • Pyramidal layer of the hippocampus
  • Cerebellar Purkinje layer

and the α2C adrenergic receptor is localised in the CNS structures:[2]

  • Midbrain
  • Thalamus
  • Amygdala
  • Dorsal root ganglia
  • Olfactory system
  • Hippocampus
  • Cerebral cortex
  • Basal ganglia
  • Substantia nigra
  • Ventral tegmentum

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.[3] 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.[3] The α2-adrenergic receptor binds both norepinephrine released by sympathetic postganglionic fibers and epinephrine (adrenaline) released by the adrenal medulla, binding norepinephrine with slightly higher affinity.[4] 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 veterinary anaesthesia where they affect sedation, muscle relaxation and analgesia through effects on the central nervous system (CNS).[5]

General

Common effects include:

Individual

Individual actions of the α2 receptor include:

Signaling cascade

The α subunit of an inhibitory G protein - Gi dissociates from the G protein,[16] 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,[13] where transmitters inhibit further release by homotropic effects.

Ligands
Agonists
Partial agonists
Antagonists
Binding affinity (Ki in nM) and clinical data on a number of alpha-2 ligands[22][23][24][25]
Drugα1Aα1Bα1Dα2Aα2Bα2CIndication(s)Route of AdministrationBioavailabilityElimination half-lifeMetabolising enzymesProtein binding
Agonists
Clonidine316.23316.23125.8942.92106.31233.1Hypertension, ADHD, analgesia, sedationOral, epidural, transdermal75-85% (IR), 89% (XR)12-16 hCYP2D620-40%
Dexmedetomidine199.53316.2379.236.1318.4637.72Procedural and ICU sedationIV100%6 minutes94%
Guanfacine???71.811200.22505.2Hypertension, ADHDOral80-100% (IR), 58% (XR)17 h (IR), 18 h (XR)CYP3A470%
Xylazine???5754.43467.4>10000Veterinary sedation?????
Xylometazoline???15.141047.13128.8Nasal congestionIntranasal????
Antagonists
Asenapine1.2??1.20.321.2Schizophrenia, bipolar disorderSublingual35%24 hCYP1A2 & UGT1A495%
Clozapine1.627?37256Treatment-resistant schizophreniaOral50-60%12 hCYP1A2, CYP3A4, CYP2D697%
Mianserin74??4.8273.8DepressionOral20%21-61 hCYP3A495%
Mirtazapine500??20?18DepressionOral50%20-40 hCYP1A2, CYP2D6, CYP3A485%

Agonists
Main article: alpha-adrenergic agonist

Norepinephrine has higher affinity for the α2 receptor than has epinephrine, and therefore relates less to the latter's functions.[13] Nonselective α2 agonists include the antihypertensive drug clonidine,[13] which can be used to lower blood pressure and to reduce hot flashes associated with menopause. 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;[26] clonidine also helps alleviate symptoms of opioid withdrawal.[27] 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.[28] 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 α2A and α2B subtypes.[29][30]

Antagonists
Main article: alpha blocker

Nonselective α blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan*[13](experimental),[31] and SB-269,970.

Yohimbine*[13] is a relatively selective alpha-2 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.

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See also

References
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