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J. Biol. Chem., Vol. 276, Issue 17, 13941-13948, April 27, 2001
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From the Division of Nephrology, Department of Medicine, University
of Florida, Gainesville, Florida 32610
The Ca2+-sensing receptor (CaR)
stimulates a number of phospholipase activities, but the specific
phospholipases and the mechanisms by which the CaR activates them are
not defined. We investigated regulation of phospholipase A2
(PLA2) by the Ca2+-sensing receptor (CaR) in
human embryonic kidney 293 cells that express either the wild-type
receptor or a nonfunctional mutant (R796W) CaR. The PLA2
activity was attributable to cytosolic PLA2 (cPLA2) based on its inhibition by arachidonyl
trifluoromethyl ketone, lack of inhibition by bromoenol lactone, and
enhancement of the CaR-stimulated phospholipase activity by
coexpression of a cDNA encoding the 85-kDa human cPLA2.
No CaR-stimulated cPLA2 activity was found in the cells
that expressed the mutant CaR. Pertussis toxin treatment had a minimal
effect on CaR-stimulated arachidonic acid release and the
CaR-stimulated rise in intracellular Ca2+
(Ca2+i), whereas inhibition of phospholipase C
(PLC) with U73122 completely inhibited CaR-stimulated PLC and
cPLA2 activities. CaR-stimulated PLC activity was inhibited
by expression of RGS4, an RGS (Regulator of G
protein Signaling) protein that inhibits G
The Ca2+-sensing Receptor Activates Cytosolic
Phospholipase A2 via a
Gq
-dependent ERK-independent Pathway*
q
activity. CaR-stimulated cPLA2 activity was inhibited 80% by chelation of extracellular Ca2+ and depletion of
intracellular Ca2+ with EGTA and inhibited 90% by
treatment with W7, a calmodulin inhibitor, or with KN-93, an inhibitor
of Ca2+, calmodulin-dependent protein kinases.
Chemical inhibitors of the ERK activator, MEK, and a dominant negative
MEK, MEKK97R, had no effect on CaR-stimulated
cPLA2 activity but inhibited CaR-stimulated ERK activity.
These results demonstrate that the CaR activates cPLA2 via
a Gq, PLC, Ca2+-CaM, and
calmodulin-dependent protein kinase-dependent pathway that
is independent the ERK pathway.
*
This work was supported by National Institutes of Health
Grant DK41726, the American Heart Association (to C. H.), and the National Kidney Foundation (to N. S. and H. A.).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, Louis Stokes VAMC, Case-Western Reserve University, 10701 East Blvd., Cleveland, OH 44106. Tel.: 216-791-3800, ext. 4660; Fax; 216-421-3025.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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