Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough

Abstract

α2-Adrenergic receptors mediate part of the diverse biological effects of the endogenous catecholamines epinephrine and norepinephrine. Three distinct subtypes of α2-adrenergic receptors, α2A, α2B, α2C, have been identified from multiple species. Because of the lack of sufficiently subtype-selective ligands, the specific biological functions of these receptor subtypes were largely unknown until recently. Gene-targeted mice carrying deletions in the genes encoding for individual α2-receptor subtypes have added important new insight into the physiological significance of adrenergic receptor diversity. Two different strategies have emerged to regulate adrenergic signal transduction. Some biological functions are controlled by two counteracting α2-receptor subtypes, e.g., α2A-receptors decrease sympathetic outflow and blood pressure, whereas the α2B-subtype increases blood pressure. Other biological functions are regulated by synergistic α2-receptor subtypes. The inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves also requires two receptor subtypes, α2A and α2C. Similarly, nociception is controlled at several levels by one of the three α2-receptor subtypes. Further investigation of the specific function of α2-subtypes will greatly enhance our understanding of the relevance of closely related receptor proteins and point out novel therapeutic strategies for subtype-selective drug development.