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Differential Effects of Gq, G14, and G15 on Vascular Smooth Muscle Cell Survival and Gene Expression Profiles

Department of Pharmacology (R.D.P., K.B.H., A.L., R.B.F., K.X., C.J.L., T.J.M., J.R.H.) and Biomolecular Computing Resource (T.T.L., K.G.), Emory University School of Medicine, Atlanta, Georgia

Gq family members (Gq, G11, G14, and G15/16) stimulate phospholipase C (PLC) 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 Gq, G14, and G15 and their cellular responses in vascular smooth muscle cells (VSMC). Constitutively active forms of Gq, G14, or G15 elicit markedly different responses when introduced to VSMC. Whereas each G stimulated PLC to similar extents when expressed at equal protein levels, Gq and G14 but not G15 initiated profound cell death within 48 h. This response was the result of activation of apoptotic pathways, because Gq and G14, but not G15, stimulated caspase-3 activation and did not alter phospho-Akt, a regulator of cell survival pathways. Gq and G14 stimulate nuclear factor of activated T cell (NFAT) activation in VSMC, but G-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 Gq, G14, and G15 each elicit markedly different profiles of altered gene sets in VSMC after 24 h. Whereas all three G stimulated changes (2-fold) in 50 shared mRNA, Gq and G14 (but not G15) stimulated changes in 221 shared mRNA, many of which are reported to be pro-apoptotic and/or involved with TNF- signaling. We were surprised to find that each G also stimulated changes in nonoverlapping G-specific gene sets. These findings demonstrate that Gq family members activate both overlapping and distinct signaling pathways and are more functionally diverse than previously thought.

Address correspondence to: Dr. John R. Hepler, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. Email: jhepler{at}emory.edu