In Vivo Mutation of the α2A-Adrenergic Receptor by Homologous Recombination Reveals the Role of This Receptor Subtype in Multiple Physiological Processes

Publisher Summary α 2 -Adrenergic receptors ( α 2 ARs) are broadly associated with inhibitory actions of norepinephrine and epinephrine. Studies with drugs designed as α 2 AR agonists and antagonists have shown that α 2 ARs participate in a wide range of central nervous system activities, including central regulation of blood pressure, sedation and analgesia, control of affect, and modulation of pituitary hormone release. In the periphery, α 2 ARs inhibit neurotransmitter release from peripheral nervous system neuronal terminals, inhibit insulin secretion by pancreatic β cells, and participate in the regulation of water and electrolyte balance in the kidney. The α 2 ARs that elicit these varied responses represent a structural and functional family of receptor subtypes defined by pharmacological measurements and molecular cloning. Interest of studies has been to establish a mouse line that expressed a mutant α 2A AR receptor with selectively altered signal transduction capabilities. Studies have shown that mutation of the highly conserved aspartate residue at position 79 in the α 2A AR to asparagine (D79N) results in a receptor that is uncoupled from a single signaling pathway. In this purpose the two-step “hit and run” gene-targeting approach is successfully used in mouse embryonic stem cells to establish a mouse line with this D79N α 2A AR mutation. Such studies reveal that the α 2A AR subtype has a role central to several of the clinically desirable effects of α 2A R agonists, suggesting that these functions cannot be separated by administering subtype-specific drugs. Null mutation of the α 2B AR subtype has revealed that this subtype mediates the increase in blood pressure immediately following α 2A R agonist administration. Thus, drugs that are selective for the α 2A AR subtype relative to the α 2B AR subtype may hold promise as improved antihypertensive agents. Sedative side effects might be eliminated if high-affinity partial agonists are developed, especially if higher receptor occupancy is needed to evoke sedation in contrast to hypotension.