Peavy, RD Hubbard, KB Lau, A Fields, RB Xu, KM Lee, CJ Lee, TT Gernert, K Murphy, TJ Hepler, JR 2024-01-21T05:02:29Z 2024-01-21T05:02:29Z 2021-09-01 2005-06 0026-895X https://pubs.kist.re.kr/handle/201004/136445 Gq alpha family members (Gq alpha, G11 alpha, G14 alpha, and G15/16 alpha) stimulate phospholipase C beta (PLC beta) 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 alpha, G14 alpha, and G15 alpha and their cellular responses in vascular smooth muscle cells (VSMC). Constitutively active forms of Gq alpha, G14 alpha, or G15 alpha elicit markedly different responses when introduced to VSMC. Whereas each G alpha stimulated PLC beta to similar extents when expressed at equal protein levels, Gq alpha and G14 alpha but not G15 alpha initiated profound cell death within 48 h. This response was the result of activation of apoptotic pathways, because Gq alpha and G14 alpha, but not G15 alpha, stimulated caspase-3 activation and did not alter phospho-Akt, a regulator of cell survival pathways. Gq alpha and G14 alpha stimulate nuclear factor of activated T cell (NFAT) activation in VSMC, but G alpha-induced cell death seems independent of PKC, InsP(3)/Ca2+, and NFAT, in that pharmacological inhibitors of these pathways did not block cell death. Gene expression analysis indicates that Gq alpha, G14 alpha, and G15 alpha each elicit markedly different profiles of altered gene sets in VSMC after 24 h. Whereas all three G alpha stimulated changes (>= 2-fold) in 50 shared mRNA, Gq alpha and G14 alpha (but not G15 alpha) 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 G alpha also stimulated changes in nonoverlapping G alpha-specific gene sets. These findings demonstrate that Gq alpha family members activate both overlapping and distinct signaling pathways and are more functionally diverse than previously thought. English AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ACTIVATED PROTEIN-KINASE NECROSIS-FACTOR-ALPHA TRANSFECTED PC12 CELLS GROWTH-FACTOR RECEPTOR DEFICIENT G ALPHA(16) PHOSPHOLIPASE-C CARDIOMYOCYTE APOPTOSIS ENDOTHELIAL-CELLS PROBE LEVEL PATHWAYS Differential effects of Gq alpha, G14 alpha, and G15 alpha on vascular smooth muscle cell survival and gene expression profiles Article 10.1124/mol.104.007799 1 MOLECULAR PHARMACOLOGY, v.67, no.6, pp.2102 - 2114 MOLECULAR PHARMACOLOGY 67 6 2102 2114 scie scopus 000229141200031 Pharmacology & Pharmacy Pharmacology & Pharmacy Article ACTIVATED PROTEIN-KINASE NECROSIS-FACTOR-ALPHA TRANSFECTED PC12 CELLS GROWTH-FACTOR RECEPTOR DEFICIENT G ALPHA(16) PHOSPHOLIPASE-C CARDIOMYOCYTE APOPTOSIS ENDOTHELIAL-CELLS PROBE LEVEL PATHWAYS G-protein GPCR cell signaling