There are at least 3 different subtypes of the a2-adrenoceptor within a species: a2A, , a2B and a2C -adrenoceptors a2-adrenoceptors are usually found presynaptically Presynaptic a2 receptors inhibit the release of noradrenaline and thus serve as an important receptor in the negative feedback control of noradrenaline release. Postsynaptic a2 receptors are located on liver cells, platelets, and the smooth muscle of blood vessels. Activation of these receptors causes platelet aggregation, and blood vessel constriction.
Sympathetic nerves are present at the adventitial-medial border of arteries an increase of noradrenaline at these sites causes constriction of the arteries. a2-adrenoceptor agonists as well as a1-adrenoceptor antagonists are therefore used for the treatment of hypertension. Blockade of presynaptic a2-adrenoceptors enhances the overflow of noradrenaline from sympathetic nerves and potentiates the response to sympathetic stimulation. This can be a problem when trying to functionally study innervated a2-adrenoceptors because a2-adrenoceptor antagonists, by inhibiting pre-junctional a2-receptors, also increase neurotransmitter release and thereby mask any contribution made by post-junctional a2-adrenoceptors.
a2-adrenoceptors are of comparable size to the b-adrenoceptors but differ in structure from a1 and b by having relatively short amino and carboxyl termini, and by possessing a very long third intracellular loop. A few amino acid residues appear to be critical for agonist or antagonist binding. For example, if Phe412 of the a2A is mutated to asparagine, the affinity for several a2-adrenoceptor antagonists is reduced by several orders of magnitude. An aspartic acid in transmembrane helix 3 has been found to be neccessary for specific binding of ligands to a2-adrenoceptors. This was shown to by inducing a mutation in which Asp113 was substituted by asparagine, this resulted in the elimination of specific binding of [3H]yohimbine to the a2-adrenoceptor. Analysis with photoaffinity probes has shown that partial agonists and antagonist ligands bind to an amino acid within the fourth transmembrane-spanning helix, although the precise location of the attachment could not be determined.
The a2-adrenoceptors belong to the Gi type of G-protein which acts to inhibit adenyl cyclase the enzyme responsible for synthesising the second messenger molecule cAMP from ATP. cAMP acts by activating protein kinases which catalyse the phosphorylation of serine and threonine residues in different cellular proteins, using ATP as the source of the phosphate groups. This mechanism acts to regulate cellular functions. The cellular functions cAMP can regulate include: cell division and cell differentiation, ion transport, ion channel function which leads to changes in electrical excitability, the contractile proteins in smooth muscle, and regulation of enzymes involved in energy metabolism.
The activation of an a2-adrenoceptor by agonist causes the a2-adrenoceptor to interact with a Gi type of G protein which inhibits the action of adenyl cyclase and thus the actions of cAMP.