DIFFERENTIAL-EFFECTS OF FORSKOLIN AND 1,9-DIDEOXY-FORSKOLIN ON NICOTINIC RECEPTOR-INDUCED AND K-INDUCED RESPONSES IN CHROMAFFIN CELLS()

The diterpene forskolin inhibits nicotine-evoked chromaffin cell Ca2influx, scinderin redistribution, F-actin disassembly and catecholamin e secretion in a concentration-dependent (10-50 mu M) fashion. On the other hand, forskolin showed weak inhibitory effects when the same res ponses were elicited by K+-induced depolarization. Similar concentrati ons of 1,9-dideoxy-forskolin, a forskolin analog which does not activa te adenylate cyclase, blocked very effectively the responses evoked by either of the two stimuli. Patch-clamp (whole-cell configuration) stu dies demonstrated that both diterpenes blocked fast and reversibly pea k and total chromaffin cell nicotinic acetylcholine receptor currents, effects not mediated through adenylate cyclase activation. Moreover, both forskolin and 1,9-dideoxy-forskolin exhibited Ca2+ channel blocki ng properties. However, 1,9-dideoxy-forskolin was more potent than for skolin as a Ca2+ channel blocker. Furthermore, 1,9-dideoxy-forskolin w as also more potent than forskolin as a nicotinic acetylcholine recept or and Ca2+ channel blocker and it was mon potent as a nicotinic acety lcholine receptor blocker than Ca2+ channel blocker. The results showe d powerful cAMP-independent effects of the diterpenes and suggest caut ion in interpretation of cAMP effects on chromaffin cells when its cel lular levels are modified by forskolin. (C) 1997 Elsevier Science B.V.