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Author Notes:

Address correspondence to: Dr. John R. Hepler, 1510 Clifton Road, G205 Rollins Research Center, Atlanta, GA 30322. E-mail: jhepler@emory.edu


Research Funding:

This work was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants R01-NS049195, R01-NS37112, R01-NS039419] and by the American Heart Association [Grant 0715465B].

PAR1 and PAR2 Couple to Overlapping and Distinct Sets of G Proteins and Linked Signaling Pathways to Differentially Regulate Cell Physiology


Journal Title:

Molecular Pharmacology


Volume 77, Number 6


, Pages 1005-1015

Type of Work:

Article | Post-print: After Peer Review


The protease-activated receptors (PAR1 and PAR2) are unusual G protein-coupled receptors that are activated by distinct serine proteases and are coexpressed in many different cell types. Limited recent evidence suggests these closely related receptors regulate different physiological outputs in the same cell, although little is known about the comparative signaling pathways used by these 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. It is surprising that 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 extracellular signal-regulated kinase (ERK) 1/2 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 mitogen-activated protein kinase kinase/ERK inhibitor [1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (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.

Copyright information:

© 2010 The American Society for Pharmacology and Experimental Therapeutics

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