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Molecular Endocrinology, doi:10.1210/me.2002-0054
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Molecular Endocrinology 16 (8): 1912-1919
Copyright © 2002 by The Endocrine Society

Receptor-Mediated Adenylyl Cyclase Activation Through XL{alpha}s, the Extra-Large Variant of the Stimulatory G Protein {alpha}-Subunit

Murat Bastepe, Yasemin Gunes, Beatriz Perez-Villamil, Joy Hunzelman, Lee S. Weinstein and Harald Jüppner

Endocrine Unit (M.B., Y.G., J.H., H.J.) and Cancer Center (B.P.-V.), Massachusetts General Hospital and MassGeneral Hospital for Children (H.J.), and Harvard Medical School, Boston, Massachusetts 02114; Metabolic Diseases Branch (L.S.W.), National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Harald Jüppner, M.D., Endocrine Unit, Massachusetts General Hospital, 50 Blossom Street, WEL 5, Boston, Massachusetts 02114. E-mail: jueppner{at}helix.mgh.harvard.edu.

XL{alpha}s, the large variant of the stimulatory G protein {alpha} subunit (Gs{alpha}), is derived from GNAS1 through the use of an alternative first exon and promoter. Gs{alpha} and XL{alpha}s have distinct amino-terminal domains, but are identical over the carboxyl-terminal portion encoded by exons 2–13. XL{alpha}s can mimic some functions of Gs{alpha}, including ß{gamma} interaction and adenylyl cyclase stimulation. However, previous attempts to demonstrate coupling of XL{alpha}s to typically Gs-coupled receptors have not been successful. We now report the generation of murine cell lines that carry homozygous disruption of Gnas exon 2, and are therefore null for endogenous XL{alpha}s and Gs{alpha} (GnasE2-/E2-). GnasE2-/E2- cells transfected with plasmids encoding XL{alpha}s and different heptahelical receptors, including the ß2-adrenergic receptor and receptors for PTH, TSH, and CRF, showed agonist-mediated cAMP accumulation that was indistinguishable from that observed with cells transiently coexpressing Gs{alpha} and these receptors. Our findings thus indicate that XL{alpha}s is capable of functionally coupling to receptors that normally act via Gs{alpha}.




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