Abstract

Gqα family members (Gqα, G11α, G14α, and G15/16α) stimulate phospholipase Cβ (PLCβ) and inositol lipid signaling but differ markedly in amino acid sequence and tissue distribution predicting unappreciated functional diversity. To examine functional differences, we compared the signaling properties of Gqα, G14α, and G15α and their cellular responses in vascular smooth muscle cells (VSMC). Constitutively active forms of Gqα, G14α, or G15α elicit markedly different responses when introduced to VSMC. Whereas each Gα stimulated PLCβ to similar extents when expressed at equal protein levels, Gqα and G14α but not G15α initiated profound cell death within 48 h. This response was the result of activation of apoptotic pathways, because Gqα and G14α, but not G15α, stimulated caspase-3 activation and did not alter phospho-Akt, a regulator of cell survival pathways. Gqα and G14α stimulate nuclear factor of activated T cell (NFAT) activation in VSMC, but Gα-induced cell death seems independent of PKC, InsP₃/Ca²⁺, and NFAT, in that pharmacological inhibitors of these pathways did not block cell death. Gene expression analysis indicates that Gqα, G14α, and G15α each elicit markedly different profiles of altered gene sets in VSMC after 24 h. Whereas all three Gα stimulated changes (≥2-fold) in 50 shared mRNA, Gqα and G14α (but not G15α) stimulated changes in 221 shared mRNA, many of which are reported to be pro-apoptotic and/or involved with TNF-α signaling. We were surprised to find that each Gα also stimulated changes in nonoverlapping Gα-specific gene sets. These findings demonstrate that Gqα family members activate both overlapping and distinct signaling pathways and are more functionally diverse than previously thought.