TY - JOUR T1 - PAR1 and PAR2 couple to overlapping and distinct sets of G proteins and linked signaling pathways to differentially regulate cell physiology JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.062018 SP - mol.109.062018 AU - Kelly L. McCoy AU - Stephen F. Traynelis AU - John R. Hepler Y1 - 2010/01/01 UR - http://molpharm.aspetjournals.org/content/early/2010/03/09/mol.109.062018.abstract N2 - The protease-activated receptors (PAR1 and PAR2) are unusual G protein-coupled receptors that are activated by distinct serine proteases and are co-expressed in many different cell types. Limited recent evidence suggests these receptors regulate different physiological outputs in the same cell, though little is known about the comparative signaling pathways utilized by these related receptors. Here we report that PAR1 and PAR2 couple to overlapping and distinct sets of G proteins to regulate receptor-specific signaling pathways involved in cell migration. In functionally PAR-null COS-7 cells, ectopically expressed PAR1 and PAR2 both form stable complexes with Gαq, Gα11, Gα14, Gα12 and Gα13. Surprisingly, PAR1 but not PAR2 coupled to Gαo, Gαi1 and Gαi2. Consistent with these observations, PAR1 and PAR2 stimulation of inositol phosphate production and RhoA activation was blocked by specific inhibitors of Gq/11 and G12/13 signaling, respectively. Both receptors stimulated ERK1/2 phosphorylation, but only PAR1 inhibited adenylyl cyclase activity, and pertussis toxin blocked PAR1 effects on both adenylyl cyclase and ERK1/2 signaling. Neu7 astrocytes express native PAR1 and PAR2 receptors that activate inositol phosphate, RhoA, and ERK1/2 signaling. However, only PAR1 inhibited adenylyl cyclase activity. PAR1 and PAR2 also stimulate Neu7 cell migration. PAR1 effects on ERK1/2 phosphorylation and cell migration were blocked both by pertussis toxin and by the MEK/ERK inhibitor (U0126), whereas PAR2 effects were only blocked by U0126. These studies demonstrate that PAR1 and PAR2 physically and functionally link to overlapping and distinct profiles of G proteins to differentially regulate downstream signaling pathways and cell physiology.The American Society for Pharmacology and Experimental Therapeutics ER -