There are at least 3 different subtypes of the a₂-adrenoceptor within a species: a_2A, , a_2B and a_2C -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 a_2A 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 G_i 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 G_i type of G protein which inhibits the action of adenyl cyclase and thus the actions of cAMP.