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J. Biol. Chem., Vol. 278, Issue 16, 14379-14386, April 18, 2003
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From the Department of Pharmacology, College of Medicine,
University of Illinois, Chicago, Illinois 60612
G2A, a G protein-coupled receptor for
which lysophosphatidylcholine (LPC) is a high affinity ligand, belongs
to a newly defined lysophospholipid receptor subfamily. Expression of
G2A is transcriptionally up-regulated by stress-inducing and
cell-damaging agents, and ectopic expression of G2A leads to growth
inhibition. However, the G proteins that functionally couple to G2A
have not been elucidated in detail. We report here that G2A ligand
independently stimulates the accumulation of both inositol
phosphates and cAMP. LPC does not further enhance inositol
phosphate accumulation but dose-dependently augments
intracellular cAMP concentration. Expression of
G
The Lysophospholipid Receptor G2A Activates a Specific
Combination of G Proteins and Promotes Apoptosis*
and
q and G13 with G2A potentiates
G2A-mediated activation of a NF-
B-luciferase reporter. These results
demonstrate that G2A differentially couples to multiple G proteins
including Gs, Gq, and G13,
depending on whether it is bound to ligand. G2A-transfected HeLa cells
display apoptotic signs including membrane blebbing, nuclear
condensation, and reduction of mitochondrial membrane potential.
Furthermore, G2A-induced apoptosis can be rescued by the caspase
inhibitors, z-vad-fmk and CrmA. Although apoptosis occurs
without LPC stimulation, LPC further enhances G2A-mediated apoptosis
and correlates with its ability to induce cAMP elevation in both HeLa
cells and primary lymphocytes. Rescue from G2A-induced apoptosis
was achieved by co-expression of a G12/13-specific
inhibitor, p115RGS (regulator of G protein
signaling), in combination with
2',5'-dideoxyadenosine treatment. These results
demonstrate the ability of G2A to activate a specific combination of G
proteins, and that G2A/LPC-induced apoptosis involves both
G13- and Gs-mediated pathways.
*
This work was supported in part by National Institutes of
Health Grant AI40176.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.
Recipient of a predoctoral fellowship from the American Heart
Association, Midwest Affiliate.
§
To whom correspondence should be addressed. Tel.: 312-996-5087;
Fax: 312-996-7857; E-mail: yer@uic.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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