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, 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 G(βγ) dimers, implying a role for the G(i/o) proteins and especially G(βγ) dimers in the cannabinoid-induced superactivation of AC.