Gqalpha family members (Gqalpha, G11alpha, G14alpha, and G15/16alpha) stimulate phospholipase Cbeta (PLCbeta) 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 Gqalpha, G14alpha, and G15alpha and their cellular responses in vascular smooth muscle cells (VSMC). Constitutively active forms of Gqalpha, G14alpha, or G15alpha elicit markedly different responses when introduced to VSMC. Whereas each Galpha stimulated PLCbeta to similar extents when expressed at equal protein levels, Gqalpha and G14alpha but not G15alpha initiated profound cell death within 48 h. This response was the result of activation of apoptotic pathways, because Gqalpha and G14alpha, but not G15alpha, stimulated caspase-3 activation and did not alter phospho-Akt, a regulator of cell survival pathways. Gqalpha and G14alpha stimulate nuclear factor of activated T cell (NFAT) activation in VSMC, but Galpha-induced cell death seems independent of PKC, InsP(3)/Ca(2+), and NFAT, in that pharmacological inhibitors of these pathways did not block cell death. Gene expression analysis indicates that Gqalpha, G14alpha, and G15alpha each elicit markedly different profiles of altered gene sets in VSMC after 24 h. Whereas all three Galpha stimulated changes (> or =2-fold) in 50 shared mRNA, Gqalpha and G14alpha (but not G15alpha) stimulated changes in 221 shared mRNA, many of which are reported to be pro-apoptotic and/or involved with TNF-alpha signaling. We were surprised to find that each Galpha also stimulated changes in nonoverlapping Galpha-specific gene sets. These findings demonstrate that Gqalpha family members activate both overlapping and distinct signaling pathways and are more functionally diverse than previously thought.