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J. Biol. Chem., Vol. 282, Issue 34, 25030-25040, August 24, 2007

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Complex Formation with the Type B -Aminobutyric Acid Receptor Affects the Expression and Signal Transduction of the Extracellular Calcium-sensing Receptor

STUDIES WITH HEK-293 CELLS AND NEURONS^*

Wenhan Chang¹, Chialing Tu, Zhiqiang Cheng, Luis Rodriguez, Tsui-Hua Chen, Martin Gassmann, Bernhard Bettler, Marta Margeta^¶, Lily Y. Jan^||, and Dolores Shoback

From the Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, California 94121, Pharmazentrum, Institute of Physiology, University of Basel, CH-4056 Basel, Switzerland, the ^¶Department of Pathology, University of California, San Francisco, California 94143, and the ^||Departments of Physiology, Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, California 94158

We co-immunoprecipitated the Ca²⁺-sensing receptor (CaR) and type B -aminobutyric acid receptor (GABA-B-R) from human embryonic kidney (HEK)-293 cells expressing these receptors and from brain lysates where both receptors are present. CaRs extensively co-localized with the two subunits of the GABA-B-R (R1 and R2) in HEK-293 cell membranes and intracellular organelles. Coexpressing CaRs and GABA-B-R1s in HEK-293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [Ca²⁺] ([Ca²⁺]_e). In contrast, coexpressing CaRs and GABA-B-R2s enhanced CaR expression and signaling responses to raising [Ca²⁺]_e. The latter effects of the GABA-B-R2 on the CaR were blunted by coexpressing the GABA-B-R1. Coexpressing the CaR with GABA-B-R1 or R2 enhanced the total cellular and cell surface expression of the GABA-B-R1 or R2, respectively. Studies with truncated CaRs indicated that the N-terminal extracellular domain of the CaR participated in the interaction of the CaR with the GABA-B-R1 and R2. In cultured mouse hippocampal neurons, CaRs co-localized with the GABA-B-R1 and R2. CaRs and GABA-B-R1s also co-immunoprecipitated from brain lysates. The expression of the CaR was increased in lysates from GABA-B-R1 knock-out mouse brains and in cultured hippocampal neurons with their GABA-B-R1 genes deleted in vitro. Thus, CaRs and GABA-B-R subunits can form heteromeric complexes in cells, and their interactions affect cell surface expression and signaling of CaR, which may contribute to extracellular Ca²⁺-dependent receptor activation in target tissues.

Received for publication, January 31, 2007 , and in revised form, May 16, 2007.

^* This work was supported by National Institutes of Health Grants RO1 AG 21353 (to W. C.) and R21 AR 054441 (to W. C.), by the Department of Veterans Affairs Merit Review (to D. S.) and Research Education Advancement Program in Bone Disease (to W. C. and D. S.), and by Swiss Science Foundation Grant 3100-067100.01 (to B. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Endocrine Research Unit, 111N San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121. Tel.: 415-750-2089; Fax: 415-750-6929; E-mail: Wenhan.Chang{at}ucsf.edu.

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				Z. Cheng, C. Tu, L. Rodriguez, T.-H. Chen, M. M. Dvorak, M. Margeta, M. Gassmann, B. Bettler, D. Shoback, and W. Chang Type B {gamma}-Aminobutyric Acid Receptors Modulate the Function of the Extracellular Ca2+-Sensing Receptor and Cell Differentiation in Murine Growth Plate Chondrocytes Endocrinology, October 1, 2007; 148(10): 4984 - 4992. [Abstract] [Full Text] [PDF]