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.
- Brainstem (especially the locus coeruleus)
- Spinal cord
- Cerebral cortex
Whereas the α2B adrenergic receptor is localised in the following CNS structures:
- Olfactory system
- Pyramidal layer of the hippocampus
- Cerebellar purkinje layer
and the α2C adrenergic receptor is localised in the CNS structures:
- Dorsal root ganglia
- Olfactory system
- Cerebral cortex
- Basal ganglia
- Substantia nigra
- Ventral tegmentum
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).
Common effects include:
- Suppression of release of norepinephrine (noradrenaline) by negative feedback.
- Transient hypertension (increase in blood pressure), followed by a sustained hypotension (decrease in blood pressure).
- Vasoconstriction of certain 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
- Constriction of some vascular smooth muscle
- Venoconstriction of veins
- Decrease motility of smooth muscle in gastrointestinal tract
- Inhibition of lipolysis
- Facilitation of the cognitive functions associated with the prefrontal cortex (PFC; working memory, attention, executive functioning, etc.)
Individual actions of the α2 receptor include:
- Mediates synaptic transmission in pre- and postsynaptic nerve terminals
- 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
- Decreased secretion from salivary gland
- Relax gastrointestinal tract (presynaptic effect)
- Decreased aqueous humor fluid production from the ciliary body
The α subunit of an inhibitory G protein - Gi 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.
|Drug||α1A||α1B||α1D||α2A||α2B||α2C||Indication(s)||Route of Administration||Bioavailability||Elimination half-life||Metabolising enzymes||Protein binding|
|Clonidine||316.23||316.23||125.89||42.92||106.31||233.1||Hypertension, ADHD, analgesia, sedation||Oral, epidural, transdermal||75-85% (IR), 89% (XR)||12-16 h||?||20-40%|
|Dexmedetomidine||199.53||316.23||79.23||6.13||18.46||37.72||Procedural and ICU sedation||IV||100%||6 minutes||94%|
|Guanfacine||?||?||?||71.81||1200.2||2505.2||Hypertension, ADHD||Oral||80-100% (IR), 58% (XR)||17 h (IR), 18 h (XR)||CYP3A4||70%|
|Asenapine||1.2||?||?||1.2||0.32||1.2||Schizophrenia, bipolar disorder||Sublingual||35%||24 h||CYP1A2 & UGT1A4||95%|
|Clozapine||1.62||7||?||37||25||6||Treatment-resistant schizophrenia||Oral||50-60%||12 h||CYP1A2, CYP3A4, CYP2D6||97%|
|Mirtazapine||500||?||?||20||?||18||Depression||Oral||50%||20-40 h||CYP1A2, CYP2D6, CYP3A4||85%|
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.
α2A selective agonists include guanfacine (an antihypertensive) and Brimonidine (UK 14,304).
(R)-3-nitrobiphenyline is an α2C selective agonist.
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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