Acute and chronic activation of the mu-opioid receptor with the endogenousligand endomorphin differentially regulates adenylyl cyclase isozymes

While acute activation of G(i/o)-coupled receptors leads to inhibition of a denylyl cyclase, chronic activation of such receptors produces an increase in cyclic AMP accumulation, particularly evident upon withdrawal of the inh ibitory agonist. This phenomenon has been referred to as adenylyl cyclase s uperactivation and is believed to play an important role in opiate addictio n. Nine adenylyl cyclase isozymes have been recently identified and shown b y us to be differentially regulated by acute and chronic inhibitory recepto r activation Using COS-7 cells cotransfected with various adenylyl cyclase isozymes, we examined here whether the endomorphins (the most recently disc overed of the four classes of endogenous opioid peptides, and which interac t selectively with the I-I receptor) are able to induce inhibition/superact ivation of representatives from the various adenylyl cyclase isozyme classe s. Here, we show that adenylyl cyclase types I and V were inhibited by acut e endomorphin application and superactivated upon chronic exposure, while a denylyl cyclase type II was stimulated by acute and "superinhibited'' by ch ronic endomorphin exposure. These results show that the endomorphins are ca pable of regulating adenylyl cyclase activity and that different adenylyl c yclase isozymes respond differently to these endogenous ligands. (C) 2000 E lsevier Science Ltd. All rights reserved.