Differential superactivation of adenylyl cyclase isozymes after chronic activation of the CB1 cannabinoid receptor

Many types of cells exhibit increased adenylyl cyclase (AC) activity after chronic agonist treatment of G(i/o)-coupled receptors. This phenomenon, def ined as AC superactivation or sensitization, has mostly been studied for th e opioid receptors and is implicated in opiate addiction. Here we show that this phenomenon is also observed on chronic activation of the CB1 cannabin oid receptor. Moreover, using COS-7 cells cotransfected with CB1 receptor a nd individual AC isozymes, we could show selective superactivation of AC ty pes 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 depen dent on the AC stimulator used. No superactivation of AC types II, IV, or V II was observed in COS-7 cells cotransfected with CB1. The superactivation of AC type V was abolished by pretreatment with pertussis toxin and by cotr ansfection with the carboxy terminus of beta-adrenergic receptor kinase, wh ich serves as a scavenger of G(beta gamma) dimers, implying a role for the G(i/o) proteins and especially G(beta gamma) dimers in the cannabinoid-indu ced superactivation of AC.