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2-Adrenergic Receptor Confer Spontaneous Activity of the Receptor
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (K.C., D.Y., S.-J.Z., H.C., R.-P.X.); and Department of Molecular and Cellular Physiology, Stanford University Medical Center, Stanford, California (Y.X., B.K.K.)
It is well established that the 
2-adrenergic receptor (2-AR) exhibits a robust ligand-independent activity, whereas this property is considerably weaker in the closely related 1-AR subtype. To identify the potential domain(s) of 2-AR responsible for the spontaneous receptor activation, we created three chimeras in which the third intracellular loop (1/2-Li3) or the carboxyl terminus (1/2-CT) or both domains (1/2-Li3CT) of 1-AR are replaced by the corresponding parts of the 2-AR. Using adenoviral gene transfer, we individually expressed these 1/2-AR chimeras in mouse cardiomyocytes lacking both native 1-AR and 2-AR (1/2 double knockout), and examined their possible spontaneous activities. Overexpression of these 1/2-AR chimeras markedly elevated basal cAMP accumulation and myocyte contractility in the absence of agonist stimulation compared with those infected by a control adenovirus expressing -galactosidase or an adenovirus expressing wild type 1-AR. These effects were fully reversed by a 2-AR inverse agonist, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551; 5 x 10-7 M), regardless of inhibition of Gi with pertussis toxin, but not by a panel of 1-AR antagonists, including [2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2-propanolmethanesulfonate (CGP20712A), betaxolol, bisoprolol, and metoprolol. Furthermore, we have shown that the C-terminal postsynaptic density 95/disc-large/ZO-1 (PDZ) motif of 1-AR is not responsible for the lack of 1-AR spontaneous activation, although it has been known that the 1-AR PDZ motif prevents the receptor from undergoing agonist-induced trafficking and Gi coupling in cardiomyocytes. Taken together, the present results indicate that both the third intracellular loop and the C terminus are involved in 2-AR spontaneous activation and that either domain seems to be sufficient to confer the receptor spontaneous activity.
Address correspondence to: Dr. Rui-Ping Xiao, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. E-mail: xiaor{at}grc.nia.nih.gov
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