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

Abstract

Alpha(2)-adrenergic receptors mediate part of the diverse biological effects of the endogenous catecholamines epinephrine and norepinephrine. Three distinct subtypes of alpha(2)-adrenergic receptors, alpha(2A), alpha(2B), alpha(2C), 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 alpha(2)-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 alpha(2)-receptor subtypes, e.g., alpha(2A)-receptors decrease sympathetic outflow and blood pressure, whereas the alpha(2B)-subtype increases blood pressure. Other biological functions are regulated by synergistic alpha(2)-receptor subtypes. The inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves also requires two receptor subtypes, alpha(2A) and alpha(2C). Similarly, nociception is controlled at several levels by one of the three alpha(2)-receptor subtypes. Further investigation of the specific function of alpha(2)-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.

Alpha2A-Adrenoceptors are Important Modulators of the Effects of D-Amphetamine on Startle Reactivity and Brain Monoamines

“…Recent studies on gene-targeted mice have confirmed that non-a 2A -AR subtypes also are involved in the autoreceptor function (for a review, see Philipp et al, 2002). This was also supported by the current study showing that, although statistically significant only in the cortex, D-amph supplementation with Ati tended to cause an additional NE decrease and an MHPG increase in a 2A -KO mice, too.…”

Alpha-adrenoceptor gene variants and autonomic nervous system function in a young healthy Japanese population

“…The a 2C -AR subtype, as well as the a 2A -AR, participated in a negative feed-back loop regulating norepinephrine release (Brede et al 2003;Philipp et al 2002). Studies in gene-targeted mice have demonstrated that disruption of a 2C -AR causes increased circulating catecholamine levels, which will consequently lead to enhanced cardiac b-AR signaling, development of dilated cardiomyopathy, and increased mortality resulting from heart failure .…”

“…Among three subtypes of a 1 -ARs, the a 1A -AR is the predominant subtype in both the heart and vasculature and is a major contributor involved in the sympathetic regulation of blood pressure and peripheral vascular resistance (Guimaraes and Moura 2001;Tanoue et al 2002). Meanwhile, a 2 -ARs are important regulators of sympathetic tone, neurotransmitter release, blood pressure, and lipolysis in fat tissue (Lafontan and Berlan 1995;Philipp et al 2002). They are widely expressed in the human central and peripheral nervous systems, and a 2A -and a 2C -AR are presynaptic receptor subtypes that contribute to feedback control of norepinephrine release from sympathetic nerves (Brede et al , 2003Philipp et al 2002).…”

“…Meanwhile, a 2 -ARs are important regulators of sympathetic tone, neurotransmitter release, blood pressure, and lipolysis in fat tissue (Lafontan and Berlan 1995;Philipp et al 2002). They are widely expressed in the human central and peripheral nervous systems, and a 2A -and a 2C -AR are presynaptic receptor subtypes that contribute to feedback control of norepinephrine release from sympathetic nerves (Brede et al , 2003Philipp et al 2002).…”

Regulation of α2AR trafficking and signaling by interacting proteins

“…Intriguingly, only agonist activation of the α 2A but not the α 2B AR subtype can cause this effect in a detectable fashion, despite the fact that both subtypes interact with spinophilin [89]. This subtype-selective enrichment of spinophilin may represent a mechanism contributing to subtype signaling diversity between the α 2A and the α 2B AR, which may serve as a base for different physiological functions elicited by these two subtypes [90].…”