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Cannabinoid receptor-interacting protein 1a modulates CB1 receptor signaling and regulation.
Smith, Tricia H; Blume, Lawrence C; Straiker, Alex; Cox, Jordan O; David, Bethany G; McVoy, Julie R Secor; Sayers, Katherine W; Poklis, Justin L; Abdullah, Rehab A; Egertová, Michaela; Chen, Ching-Kang; Mackie, Ken; Elphick, Maurice R; Howlett, Allyn C; Selley, Dana E.
Afiliação
  • Smith TH; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Blume LC; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Straiker A; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Cox JO; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • David BG; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • McVoy JR; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Sayers KW; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Poklis JL; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Abdullah RA; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Egertová M; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Chen CK; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Mackie K; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Elphick MR; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Howlett AC; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
  • Selley DE; Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies (T.H.S., J.O.C., B.G.D., J.R.S.M., J.L.P., R.A.A., D.E.S.), Department of Anatomy and Neurobiology (K.W.S.), Department of Biochemistry and Molecular Biology (C.-K.C.), Virginia Commonwealth University School of Med
Mol Pharmacol ; 87(4): 747-65, 2015 Apr.
Article em En | MEDLINE | ID: mdl-25657338
ABSTRACT
Cannabinoid CB1 receptors (CB1Rs) mediate the presynaptic effects of endocannabinoids in the central nervous system (CNS) and most behavioral effects of exogenous cannabinoids. Cannabinoid receptor-interacting protein 1a (CRIP1a) binds to the CB1R C-terminus and can attenuate constitutive CB1R-mediated inhibition of Ca(2+) channel activity. We now demonstrate cellular colocalization of CRIP1a at neuronal elements in the CNS and show that CRIP1a inhibits both constitutive and agonist-stimulated CB1R-mediated guanine nucleotide-binding regulatory protein (G-protein) activity. Stable overexpression of CRIP1a in human embryonic kidney (HEK)-293 cells stably expressing CB1Rs (CB1-HEK), or in N18TG2 cells endogenously expressing CB1Rs, decreased CB1R-mediated G-protein activation (measured by agonist-stimulated [(35)S]GTPγS (guanylyl-5'-[O-thio]-triphosphate) binding) in both cell lines and attenuated inverse agonism by rimonabant in CB1-HEK cells. Conversely, small-interfering RNA-mediated knockdown of CRIP1a in N18TG2 cells enhanced CB1R-mediated G-protein activation. These effects were not attributable to differences in CB1R expression or endocannabinoid tone because CB1R levels did not differ between cell lines varying in CRIP1a expression, and endocannabinoid levels were undetectable (CB1-HEK) or unchanged (N18TG2) by CRIP1a overexpression. In CB1-HEK cells, 4-hour pretreatment with cannabinoid agonists downregulated CB1Rs and desensitized agonist-stimulated [(35)S]GTPγS binding. CRIP1a overexpression attenuated CB1R downregulation without altering CB1R desensitization. Finally, in cultured autaptic hippocampal neurons, CRIP1a overexpression attenuated both depolarization-induced suppression of excitation and inhibition of excitatory synaptic activity induced by exogenous application of cannabinoid but not by adenosine A1 agonists. These results confirm that CRIP1a inhibits constitutive CB1R activity and demonstrate that CRIP1a can also inhibit agonist-stimulated CB1R signaling and downregulation of CB1Rs. Thus, CRIP1a appears to act as a broad negative regulator of CB1R function.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Transporte / Receptor CB1 de Canabinoide Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Transporte / Receptor CB1 de Canabinoide Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2015 Tipo de documento: Article