Alpha 2 adrenergic receptor

Cellular localisation

The α_2A adrenergic receptor is localised in the following central nervous system (CNS) structures:

Whereas the α_2B adrenergic receptor is localised in the following CNS structures:

and the α_2C adrenergic receptor is localised in the CNS structures:

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. The α₂-adrenergic receptor binds both norepinephrine released by sympathetic postganglionic fibers and epinephrine (adrenaline) released by the adrenal medulla, binding norepinephrine (noradrenaline) with slightly higher affinity. 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).

General

Common effects include:

Individual

Individual actions of the α₂ receptor include:

Signaling cascade

The α subunit of an inhibitory G protein - G_i dissociated 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

Agonists

Norepinephrine has higher affinity for the α₂ receptor than has epinephrine, and therefore relates less to the latter's functions. 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 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 08/10/2012 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.

α_2A selective agonists include guanfacine (an antihypertensive) and Brimonidine (UK 14,304).

(R)-3-nitrobiphenyline is an α_2C selective agonist.

Antagonists

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

α_2A selective blockers include BRL-44408 and RX-821,002.

α_2B selective blockers include ARC-239 and imiloxan.

α_2C selective blockers include JP-1302 and spiroxatrine, the latter also being a serotonin 5-HT_1A antagonist.