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Adult mesenchymal stem cells support cisplatin-treated dorsal root ganglion survival
Authors:Scuteri Arianna  Donzelli Elisabetta  Ravasi Maddalena  Tredici Giovanni
Affiliation:Department of Pharmaceutical Biology, University of Regensburg, Regensburg, Germany.
Abstract:Human cannabinoid receptors 1 (hCB(1)R) and 2 (hCB(2)R) are expressed in the CNS and couple to G(i)/G(o)-proteins. The aim of this study was to compare coupling of hCB(1)R and hCB(2)R to G(alpha)(i2)beta(1)gamma(2) in Sf9 insect cells. High-affinity agonist binding at hCB(1)R, but not at hCB(2)R, was resistant to guanine nucleotides. hCB(1)R activated G(alpha)(i2)beta(1)gamma(2) much more rapidly than hCB(2)R in the [(35)S]guanosine 5'-[gamma-thio]triphosphate ([(35)S]GTPgammaS) binding assay. Moreover, hCB(1)R exhibited a higher constitutive activity than hCB(2)R as assessed by the relative inhibitory effects of inverse agonists on [(35)S]GTPgammaS binding and steady-state high-affinity GTPase activity compared to the stimulatory effects of the hCB(1/2)R agonist CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol]. G(alpha)(i2)beta(1)gamma(2) coupled to hCB(2)R exhibited higher GDP- and GTPgammaS-affinities than G(alpha)(i2)beta(1)gamma(2) coupled to hCB(1)R. NaCl effectively reduced constitutive activity of hCB(1)R but not of hCB(2)R. Collectively, hCB(1)R and hCB(2)R couple differentially to G(alpha)(i2)beta(1)gamma(2). Moreover, hCB(1)R exhibits higher constitutive activity than hCB(2)R. These differences point to distinct functions of hCB(1)R and hCB(2)R in the CNS.
Keywords:AM 251, 6-iodopravadoline   AM 630, (6-iodo-2-methyl-1-[2-4(morpholinyl)-ethyl]-[1H-indol-3-yl]-(4-methoxyphenyl)methan-none)   β2ARβ, 2-adrenoceptor   CP 55, 940, [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol]   hCB1R, human cannabinoid receptor subtype 1   hCB2R, human cannabinoid receptor subtype 2   GPCR, G-protein-coupled receptor   GTPγS, guanosine 5′-[γ-thio]triphosphate
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