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Parathyroid-Specific Double Knockout of G_q and G₁₁ -Subunits Leads to a Phenotype Resembling Germline Knockout of the Extracellular Ca²⁺-Sensing Receptor

Pharmakologisches Institut (N.W., S.O.), Universität Heidelberg, 69120 Heidelberg, Germany; and Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (E.L., P.G.R.), Surgery Branch, Center for Cancer Research, National Cancer Institute (S.K.L.), and Molecular Pathophysiology Section, National Institute on Deafness and Other Communication Disorders (A.M.S.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Nina Wettschureck, Pharmakologisches Institut der Universität Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. E-mail: nina.wettschureck{at}pharma.uni-heidelberg.de.

Germline knockout of the extracellular Ca²⁺-sensing receptor (CaR) leads to a phenotype that includes severe hypercalcemia, hyperparathyroidism, relative hypocalciuria, skeletal abnormalities, retarded growth, and early postnatal death. To investigate the role of heterotrimeric G proteins in CaR signaling, we used cre/lox technology to delete the respective -subunits of G_q and G₁₁ selectively in parathyroid cells. Mice that were PTH-Cre^+/–; Gnaq^flox/flox; Gna11^–/– (PTH-G_q/G₁₁-double knockouts) were viable, but showed all the features of germline knockout of the CaR except hypocalcuria. Our results demonstrate the critical role of both G_q and G₁₁ in mediating inhibition of PTH secretion by extracellular Ca²⁺.

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