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J. Biol. Chem., Vol. 277, Issue 23, 20293-20300, June 7, 2002
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From the Division of Nephrology, Department of Medicine, Case
Western Reserve University, Louis Stokes Veteran Affairs Medical
Center, Cleveland, Ohio 44106, and the Department of Medicine, College
of Medicine, University of Florida, Gainesville, Florida 32106
The calcium-sensing receptor (CaR) is a G
protein-coupled receptor that regulates physiological processes
including Ca2+ metabolism, Na+,
Cl
Parallel Activation of Phosphatidylinositol 4-Kinase and
Phospholipase C by the Extracellular Calcium-sensing Receptor*
,
, K+, and H20 balance, and the
growth of some epithelial cells through diverse signaling pathways.
Although many effects of CaR are mediated by the heterotrimeric
G proteins G
q and Gi, not all signaling pathways regulated by CaR have been identified. We used human embryonic
kidney (HEK)-293 cells that stably express human CaR to study the
regulation of inositol lipid metabolism by CaR. The nonfunctional
mutant CaRR796W was used as a negative control. We found
that CaR regulates phosphatidylinositol (PI) 4-kinase, the first step
in inositol lipid biosynthesis. In cells pretreated with U73122 to
inhibit phospholipase C activation and to block the degradation of PI
4,5-bisphosphate to form [3H]inositol trisphosphate
(IP3), CaR stimulated the accumulation of
[3H]PI monophosphate (PIP). Additionally, wortmannin, an
inhibitor of both PI 3-kinase and type III PI 4-kinase, blocked
CaR-stimulated accumulation of [3H]PIP and inhibited
[3H]IP3 production. CaR-stimulated inositol
lipid synthesis was attributable to PI 4-kinase and not PI 3-kinase
because CaR did not activate Akt, a downstream target of PI 3-kinase.
CaR associates with PI 4-kinase based on the findings that CaR and the
110-kDa PI 4-kinase 
can be co-immunoprecipitated with antibodies
against either CaR or PI 4-kinase. The PI-4 kinase in
co-immunoprecipitates with anti-CaR antibody was activated in
Ca2+-stimulated HEK-293 cells, which stably express the
wild type CaR. Pertussis toxin did not affect the formation of
[3H]IP3 or the rise in intracellular
Ca2+ (Handlogten, M. E., Huang, C. F., Shiraishi, N.,
Awata, H., and Miller, R. T. (2001) J. Biol. Chem.
276, 13941-13948). RGS4, an accelerator of GTPase activity of members
of the Gi and Gq families, attenuated the
CaR-stimulated PLC activation and IP3 accumulation, which
is mediated by Gq, but did not inhibit CaR-stimulated
[3H]PIP formation. In HEK-293 cells, which express wild
type CaR, Rho was enriched in immune complexes co-immunoprecipitated
with the anti-CaR antibody. C3 toxin, an inhibitor of Rho,
also inhibited the CaR-stimulated [3H]IP3
production but did not lead to CaR-stimulated [3H]PIP
formation, reflecting inhibition of PI 4-kinase. Taken together, our data demonstrate that CaR stimulates PI 4-kinase, the first step in
inositol lipid biosynthesis conversion of PI to PI 4-P by
Rho-dependent and Gq- and
Gi-independent pathways.
*
This work was supported by grants from the American Heart
Association (to C. F. H. and R. T. M.), the National Institutes of
Health (DK-41726, to R. T. M.), and the Rainbow Center for Childhood
PKD and Leonard Rosenberg Research Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Nephrology, Dept. of Medicine, Case Western Reserve University, Louis Stokes Veteran Affairs Medical Center, 10701 E. Blvd, 151W, Cleveland, OH 44106. Tel.: 216-791-3800, Ext. 5470; Fax: 216-229-8509; E-mail: cxh87@po.cwru.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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