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Mol Pharmacol
2010 Jun 01;776:1005-15. doi: 10.1124/mol.109.062018.
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PAR1 and PAR2 couple to overlapping and distinct sets of G proteins and linked signaling pathways to differentially regulate cell physiology.
McCoy KL
,
Traynelis SF
,
Hepler JR
.
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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 G alpha(q), G alpha(11), G alpha(14), G alpha(12), and G alpha(13). It is surprising that PAR1 but not PAR2 coupled to G alpha(o), G alpha(i1), and G alpha(i2). Consistent with these observations, PAR1 and PAR2 stimulation of inositol phosphate production and RhoA activation was blocked by specific inhibitors of G(q/11) and G(12/13) 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.
Aragay,
G12 requirement for thrombin-stimulated gene expression and DNA synthesis in 1321N1 astrocytoma cells.
1995, Pubmed
Aragay,
G12 requirement for thrombin-stimulated gene expression and DNA synthesis in 1321N1 astrocytoma cells.
1995,
Pubmed
Ayoub,
Real-time analysis of agonist-induced activation of protease-activated receptor 1/Galphai1 protein complex measured by bioluminescence resonance energy transfer in living cells.
2007,
Pubmed
Blackhart,
Extracellular mutations of protease-activated receptor-1 result in differential activation by thrombin and thrombin receptor agonist peptide.
2000,
Pubmed
,
Xenbase
Bünemann,
Gi protein activation in intact cells involves subunit rearrangement rather than dissociation.
2003,
Pubmed
Citro,
Phospholipase Cepsilon is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation.
2007,
Pubmed
Coughlin,
Protease-activated receptors in hemostasis, thrombosis and vascular biology.
2005,
Pubmed
Dascal,
Further characterization of the slow muscarinic responses in Xenopus oocytes.
1987,
Pubmed
,
Xenbase
DeFea,
beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2.
2000,
Pubmed
Déry,
Proteinase-activated receptors: novel mechanisms of signaling by serine proteases.
1998,
Pubmed
Fok-Seang,
An analysis of astrocytic cell lines with different abilities to promote axon growth.
1995,
Pubmed
Gerhardt,
Stimulation of the extracellular signal-regulated kinase 1/2 pathway by human beta-3 adrenergic receptor: new pharmacological profile and mechanism of activation.
1999,
Pubmed
Hains,
Application of RGS box proteins to evaluate G-protein selectivity in receptor-promoted signaling.
2004,
Pubmed
Hains,
Galpha12/13- and rho-dependent activation of phospholipase C-epsilon by lysophosphatidic acid and thrombin receptors.
2006,
Pubmed
Hamill,
Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function.
2009,
Pubmed
Hein,
Coupling mode of receptors and G proteins.
2009,
Pubmed
Hung,
The cloned platelet thrombin receptor couples to at least two distinct effectors to stimulate phosphoinositide hydrolysis and inhibit adenylyl cyclase.
1992,
Pubmed
Ishihara,
Protease-activated receptor 3 is a second thrombin receptor in humans.
1997,
Pubmed
Kelley,
Hormonal regulation of phospholipase Cepsilon through distinct and overlapping pathways involving G12 and Ras family G-proteins.
2004,
Pubmed
Klages,
Activation of G12/G13 results in shape change and Rho/Rho-kinase-mediated myosin light chain phosphorylation in mouse platelets.
1999,
Pubmed
Kramer,
Differential activation of cytosolic phospholipase A2 (cPLA2) by thrombin and thrombin receptor agonist peptide in human platelets. Evidence for activation of cPLA2 independent of the mitogen-activated protein kinases ERK1/2.
1995,
Pubmed
Lutz,
The guanine nucleotide exchange factor p63RhoGEF, a specific link between Gq/11-coupled receptor signaling and RhoA.
2005,
Pubmed
Macfarlane,
Proteinase-activated receptors.
2001,
Pubmed
Mannaioni,
Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1.
2008,
Pubmed
McLaughlin,
Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1.
2005,
Pubmed
Means,
S1P1 receptor localization confers selectivity for Gi-mediated cAMP and contractile responses.
2008,
Pubmed
Nicole,
Activation of protease-activated receptor-1 triggers astrogliosis after brain injury.
2005,
Pubmed
Nishino,
Thrombin may contribute to the pathophysiology of central nervous system injury.
1993,
Pubmed
Nürnberg,
Antagonistic regulation of neurite morphology through Gq/G11 and G12/G13.
2008,
Pubmed
Nystedt,
Molecular cloning of a potential proteinase activated receptor.
1994,
Pubmed
,
Xenbase
Offermanns,
G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets.
1994,
Pubmed
Ogino,
Direct evidence for two distinct G proteins coupling with thrombin receptors in human neuroblastoma SH-EP cells.
1996,
Pubmed
Olianas,
Proteinase-activated receptors 1 and 2 in rat olfactory system: layer-specific regulation of multiple signaling pathways in the main olfactory bulb and induction of neurite retraction in olfactory sensory neurons.
2007,
Pubmed
Oron,
Inositol 1,4,5-trisphosphate mimics muscarinic response in Xenopus oocytes.
,
Pubmed
,
Xenbase
Ossovskaya,
Protease-activated receptors: contribution to physiology and disease.
2004,
Pubmed
Pindon,
Thrombomodulin as a new marker of lesion-induced astrogliosis: involvement of thrombin through the G-protein-coupled protease-activated receptor-1.
2000,
Pubmed
Post,
Coupling of the thrombin receptor to G12 may account for selective effects of thrombin on gene expression and DNA synthesis in 1321N1 astrocytoma cells.
1996,
Pubmed
Ramachandran,
Agonist-biased signaling via proteinase activated receptor-2: differential activation of calcium and mitogen-activated protein kinase pathways.
2009,
Pubmed
Sorensen,
Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes.
2003,
Pubmed
Swift,
Role of the PAR1 receptor 8th helix in signaling: the 7-8-1 receptor activation mechanism.
2006,
Pubmed
Traynelis,
Protease-activated receptor signaling: new roles and regulatory mechanisms.
2007,
Pubmed
Vandell,
Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines.
2008,
Pubmed
Vanhauwe,
Thrombin receptors activate G(o) proteins in endothelial cells to regulate intracellular calcium and cell shape changes.
2002,
Pubmed
Verrall,
The thrombin receptor second cytoplasmic loop confers coupling to Gq-like G proteins in chimeric receptors. Additional evidence for a common transmembrane signaling and G protein coupling mechanism in G protein-coupled receptors.
1997,
Pubmed
,
Xenbase
Voss,
PAR1, but not PAR4, activates human platelets through a Gi/o/phosphoinositide-3 kinase signaling axis.
2007,
Pubmed
Vu,
Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation.
1991,
Pubmed
,
Xenbase
Wang,
Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways.
2002,
Pubmed
Xu,
Cloning and characterization of human protease-activated receptor 4.
1998,
Pubmed
