The alpha-2 (ñ<sub>2</sub>) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR) associated with the G<sub>i</sub> heterotrimeric G-protein. It consists of three homologous subtypes, ñ<sub>2A</sub>-, ñ<sub>2B</sub>-, and ñ<sub>2C</sub>-adrenergic. Some species other than humans express a fourth ñ<sub>2D</sub>-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the ñ<sub>2</sub>-adrenergic receptor in the central and peripheral nervous systems.
The ñ<sub>2A</sub> adrenergic receptor is localised in the following central nervous system (CNS) structures:
Whereas the ñ<sub>2B</sub> adrenergic receptor is localised in the following CNS structures:
and the ñ<sub>2C</sub> adrenergic receptor is localised in the CNS structures:
The ñ<sub>2</sub>-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 ñ<sub>1</sub>-adrenergic receptor. The ñ<sub>2</sub>-adrenergic receptor binds both norepinephrine released by sympathetic postganglionic fibers and epinephrine (adrenaline) released by the adrenal medulla, binding norepinephrine with slightly higher affinity. It has several general functions in common with the ñ<sub>1</sub>-adrenergic receptor, but also has specific effects of its own. Agonists (activators) of the ñ<sub>2</sub>-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, ñ<sub>2</sub>-adrenergic receptors can be localized either pre- or post-synaptically, however the majority of receptors appear to be post-synaptic. For example, the ñ<sub>2A</sub> 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 ñ<sub>2A</sub>-adrenergic agonist, guanfacine, is now used to treat prefrontal cortical cognitive disorders such as attention deficit hyperactivity disorder (ADHD).
Common effects include:
Individual actions of the ñ<sub>2</sub> receptor include:
The ñ subunit of an inhibitory G protein - G<sub>i</sub> 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.
Norepinephrine has higher affinity for the ñ<sub>2</sub> receptor than epinephrine does, and therefore relates less to the latter's functions. Nonselective ñ<sub>2</sub> agonists include the antihypertensive drug clonidine, 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 shown positive results in children with ADHD who have 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 ñ<sub>2</sub> 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 ñ<sub>2</sub> 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 ñ<sub>2</sub> adrenergic receptors because it is reversed by yohimbine, an ñ<sub>2</sub> antagonist.
ñ<sub>2A</sub> selective agonists include guanfacine (an antihypertensive) and brimonidine (UK 14,304).
(R)-3-nitrobiphenyline is an ñ<sub>2C</sub> selective agonist as well as being a weak antagonist at the ñ and ñ subtypes.
Non-selective ñ blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan (experimental), and SB-269,970.
Yohimbine is a relatively selective ñ<sub>2</sub> blocker that has been investigated as a treatment for erectile dysfunction.
Tetracyclic antidepressants mirtazapine and mianserin are also potent ñ antagonists with mirtazapine being more selective for ñ<sub>2</sub> subtype (~30-fold selective over ñ<sub>1</sub>) than mianserin (~17-fold).
ñ<sub>2A</sub> selective blockers include BRL-44408 and RX-821,002.
ñ<sub>2B</sub> selective blockers include ARC-239 and imiloxan.
ñ<sub>2C</sub> selective blockers include JP-1302 and spiroxatrine, the latter also being a serotonin 5-HT<sub>1A</sub> antagonist.