The CB1 Cannabinoid Receptor of Astrocytes Is Coupled to Sphingomyelin Hydrolysis through the Adaptor Protein Fan

  1. Cristina Sánchez1,
  2. Daniel Rueda1,
  3. Bruno Ségui2,
  4. Ismael Galve-Roperh1,
  5. Thierry Levade2 and
  6. Manuel Guzmán1
  1. 1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain (C.S., D.R., I.G.-R., M.G.); and 2Institut National de la Santé et de la Recherche Médicale U466, Laboratoire de Biochimie, Centre Hospitalier Universitaire Rangeil, Toulouse, France (B.S., T.L.)

    Abstract

    Cannabinoids exert most of their effects through the CB1 receptor. This G protein-coupled receptor signals inhibition of adenylyl cyclase, modulation of ion channels, and stimulation of mitogen- and stress-activated protein kinases. In this article, we report that Δ9-tetrahydrocannabinol (THC), the major active component of marijuana, induces sphingomyelin hydrolysis in primary astrocytes but not in other cells expressing the CB1 receptor, such as primary neurons, U373 MG astrocytoma cells, and Chinese hamster ovary cells transfected with the CB1 receptor cDNA. THC-evoked sphingomyelin breakdown in astrocytes was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoid HU-210 and was prevented by the selective CB1 antagonist SR141716. By contrast, the effect of THC was not blocked by pertussis toxin, pointing to a lack of involvement of Gi/o proteins. A role for the adaptor protein FAN in CB1 receptor-coupled sphingomyelin breakdown is supported by two observations: 1) coimmunoprecipitation experiments show that the binding of FAN to the CB1 receptor is enhanced by THC and prevented by SR141716; 2) cells expressing a dominant-negative form of FAN are refractory to THC-induced sphingomyelin breakdown. This is the first report showing that a G-protein-coupled receptor induces sphingomyelin hydrolysis through FAN and that the CB1cannabinoid receptor may signal independently of Gi/oproteins.

    Footnotes

    • Send reprint requests to: Dr. Manuel Guzmán, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain. E-mail: mgp{at}bbm1.ucm.es

    • This study was supported by grants from Comisión Interministerial de Ciencia y Tecnologı́a (PM 98/0079), Comunidad Autónoma de Madrid (CAM 08.5/0017/98), and Institut National de la Santé et de la Recherche Médicale.

    • Abbreviations:
      THC
      Δ9-tetrahydrocannabinol
      TNF
      tumor necrosis factor
      CHO
      Chinese hamster ovary
      PMSF
      phenylmethylsulfonyl fluoride
      FAN
      factor associated with neutral sphingomyelinase activation
      NSD
      neutral sphingomyelinase activation domain
      • Received October 23, 2000.
      • Accepted January 19, 2001.
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    1. Molecular Pharmacology May 1, 2001 vol. 59 no. 5 955-959
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