Common Signaling Pathways Link Activation of Murine PAR-1 LPA, and S1P Receptors to Proliferation of Astrocytes
Molecular Pharmacology. 2003-11-01; 64(5): 1199-1209
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1. Mol Pharmacol. 2003 Nov;64(5):1199-209.
Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors
to proliferation of astrocytes.
Sorensen SD(1), Nicole O, Peavy RD, Montoya LM, Lee CJ, Murphy TJ, Traynelis SF,
(1)Emory University School of Medicine, Department of Pharmacology, Rollins
Research Center, 1510 Clifton Road, Atlanta, GA 30322-3090, USA.
Receptors for the serine protease thrombin and for lysophospholipids are coupled
to G proteins and control a wide range of cellular functions, including
mitogenesis. Activators of these receptors are present in blood, and can enter
the brain during central nervous system (CNS) injury. Reactive astrogliosis, a
prominent component of CNS injury with potentially harmful consequences, may
involve proliferation of astrocytes. In this study, we have examined the
expression and activation of protease activated receptors (PARs),
lysophosphatidic acid (LPA) receptors, and sphingosine-1-phosphate (S1P)
receptors on murine astrocytes. We show that activation of these three receptor
classes can lead to astrogliosis in vivo and proliferation of astrocytes in
vitro. Cultured murine cortical astrocytes express mRNA for multiple receptor
subtypes of PAR (PAR-1-4), LPA (LPA-1-3) and S1P (S1P-1, -3, -4, and -5)
receptors. Comparison of the intracellular signaling pathways of glial PAR-1,
LPA, and S1P receptors indicates that each receptor class activates multiple
downstream signaling pathways, including Gq/11-directed inositol lipid/Ca2+
signaling, Gi/o activation of mitogen-activated protein kinases (MAPK)
(extracellular signal-regulated kinase 1/2 and stress activated protein
kinase/c-jun N-terminal kinase, but not p38), and activation of Rho pathways.
Furthermore, activation of these different receptor classes can differentially
regulate two transcription factor pathways, serum response element and nuclear
factor of activated T cells. Blockade of Gi/o signaling with pertussis toxin,
MAPK activation with 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene
(U0126), or Rho kinase signaling with
R-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane carboxamide (Y27632) can
markedly reduce the proliferative response of glial cells to PAR-1, LPA, or S1P
receptor activation, suggesting that each of these pathways is important in
coupling of receptor activation to glial proliferation.
PMID: 14573770 [Indexed for MEDLINE]