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 alpha(q) and G alpha(13) with G2A potentiates G2A-mediated activation of a NF-kappa B-luciferase reporter. These results demonstrate that G2A differentially couples to multiple G proteins including G alpha(s), G alpha(q), and G alpha(13), 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 G alpha(12/13)-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 G alpha(13)- and G alpha(s)-mediated pathways.