Adenylyl cyclase type II activity is regulated by two different mechanisms: Implications for acute and chronic opioid exposure

Abstract

Acute and chronic activation of opioid receptors differentially regulate the activity of the various adenylyl cyclase (AC) isoforms. In several AC isoforms (I, V, VI and VIII) acute opioid activation (by agonists such as morphine) leads to AC inhibition, while prolonged opioid activation leads to increase in AC activity, a phenomenon known as AC sensitization or superactivation. In several other AC isoforms (II, IV and VII), acute opioid activation leads to AC stimulation, while chronic opioid exposure inhibits AC activity, in a process, which in analogy to the term “superactivation” is referred to as “superinhibition”. AC-II is highly regulated by multiple and independent biochemical stimuli, including G βγ, G αs and PKC activation. We investigated the regulation of AC-II by G αs and by PKC under conditions of acute and chronic exposure to opioid agonists in COS-7 transfected cells. We found that acute opioid exposure led to an increase in AC-II activity by either G αs or PKC stimulation. This effect seems to be regulated by G βγ subunits, in both activation pathways, as the increase in AC-II activity was abolished by pertussis toxin treatment and by G βγ scavengers. On the other hand, while chronic opioid exposure led to a decrease in AC-II activity (“superinhibition”) upon stimulation of the G αs pathway, this superinhibition was not observed when the opioid treated cells were stimulated via PKC activation.