Inhibition of agonist-induced degradation of muscarinic cholinergic receptor by quinacrine and tetracaine--possible involvement of phospholipase A2 in receptor degradation

Abstract

Muscarinic cholinergic receptors (mAChR) are degraded on the addition of agonists through energy- and temperature-dependent processes, probably with clustering and endocytosis. Pretreatment of guinea-pig vas deferens with 0.5 mM quinacrine or 5 mM tetracaine, phospholipase A2 (PLase A2) inhibitors, inhibited the ACh-induced degradation of mAChR in the smooth muscle and kept mAChR on the surface membrane, while cocaine and procaine were not effective. On pretreatment with quinacrine or tetracaine the PLase A2 activity in the smooth muscle decreased continuously during culture without change in the contractile response of the tissue. Pretreatment with cocaine and procaine which had no significant effect on the down regulation of mAChR did not inhibit PLase A2 activity. However, activation of PLase A2 by long-term culture of the muscle with ACh and formation of endogenous inhibitor of PLase A2 were not observed under our experimental conditions. The participation of PLase A2 in the agonist-induced degradation of mAChR is discussed in the light of these findings.