Differential Superactivation of Adenylyl Cyclase Isozymes after Chronic Activation of the CB1 Cannabinoid Receptor1

  1. Man-Hee Rhee,
  2. Igal Nevo,
  3. Tomer Avidor-Reiss,
  4. Rivka Levy and
  5. Zvi Vogel
  1. Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel

    Abstract

    Many types of cells exhibit increased adenylyl cyclase (AC) activity after chronic agonist treatment of Gi/o-coupled receptors. This phenomenon, defined as AC superactivation or sensitization, has mostly been studied for the opioid receptors and is implicated in opiate addiction. Here we show that this phenomenon is also observed on chronic activation of the CB1 cannabinoid receptor. Moreover, using COS-7 cells cotransfected with CB1 receptor and individual AC isozymes, we could show selective superactivation of AC types I, III, V, VI, and VIII. The level of superactivation was dependent on the concentration of agonist and time of agonist exposure and was not dependent on the AC stimulator used. No superactivation of AC types II, IV, or VII was observed in COS-7 cells cotransfected with CB1. The superactivation of AC type V was abolished by pretreatment with pertussis toxin and by cotransfection with the carboxy terminus of β-adrenergic receptor kinase, which serves as a scavenger of Gβγ dimers, implying a role for the Gi/o proteins and especially Gβγ dimers in the cannabinoid-induced superactivation of AC.

    Footnotes

    • Send reprint requests to: Prof. Zvi Vogel, Dept. of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: zvi.vogel{at}weizmann.ac.il

    • ↵1 This work was supported by the Israel Science Foundation. Z.V. is the incumbent of the Ruth and Leonard Simon Chair for Cancer Research.

    • Abbreviations:
      G protein
      GTP-binding protein
      AC
      adenylyl cyclase
      βARK-C
      carboxy terminus of β-adrenergic receptor kinase
      DMEM
      Dulbecco's modified Eagle's medium
      FAF-BSA
      fatty acid-free bovine serum albumin
      PK
      protein kinase
      PTX
      pertussis toxin
      TSH
      thyroid-stimulating hormone
      CHO
      Chinese hamster ovary
      CHO-CB1
      CHO cells expressing rat CB1
      • Received October 14, 1999.
      • Accepted December 20, 1999.
    « Previous | Next Article »Table of Contents

    This Article

    1. Molecular Pharmacology April 1, 2000 vol. 57 no. 4 746-752
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Classifications

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 76 (5)
    1. Current Issue
    1. Alert me to new issues of Molecular Pharmacology