REGULATION OF ADENYLYL-CYCLASE BY MEMBRANE-POTENTIAL

Mammalian adenylyl cyclases possess 12 transmembrane-spanning domains and bear a superficial resemblance to certain classes of ion channels. Some evidence suggests that bacterial and sea urchin sperm adenylyl c yclases can be regulated by membrane depolarization. In the present st udy, we explored the effect of altering membrane potential on the aden ylyl cyclase activity of cerebellar granule cells with acute potassium depolarization. A biphasic stimulatory and then inhibitory response i s evoked by progressive increases in the extracellular [K]:[Na] ratio in the absence of-extracellular Ca2+. This effect does not mimic the l inear increase in membrane potential elicited under the same condition s. Instead it appears as though membrane depolarization opens L-type ( nimodipine-sensitive) Ca2+ channels, allowing the entry of Na+, which directly stimulates adenylyl cyclase activity. Gramicidin, which gener ates pores that are permeable to monovalent cations, and concurrently eliminates the membrane potential, permits a similar stimulation by ex tracellularly applied Na+. Although the results indicate no direct sen sitivity of cerebellar granule cell adenylyl cyclase to membrane poten tial, they do demonstrate that, as a result of membrane depolarization , the influx of Na+, as well as Ca2+, will elevate cAMP levels.