Differential effects of forskolin and 1,9-dideoxy-forskolin on nicotinic receptor- and K+-induced responses in chromaffin cells.
The diterpene forskolin inhibits nicotine-evoked chromaffin cell Ca2+ influx, scinderin redistribution, F-actin disassembly and catecholamine secretion in a concentration-dependent (10-50 microM) fashion. On the other hand, forskolin showed weak inhibitory effects when the same responses were elicited by K+-induced depolarization. Similar concentrations of 1,9-dideoxy-forskolin, a forskolin analog which does not activate adenylate cyclase, blocked very effectively the responses evoked by either of the two stimuli. Patch-clamp (whole-cell configuration) studies demonstrated that both diterpenes blocked fast and reversibly peak 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 blocking properties. However, 1,9-dideoxy-forskolin was more potent than forskolin as a Ca2+ channel blocker. Furthermore, 1,9-dideoxy-forskolin was also more potent than forskolin as a nicotinic acetylcholine receptor and Ca2+ channel blocker and it was more potent as a nicotinic acetylcholine receptor blocker than Ca2+ channel blocker. The results showed powerful cAMP-independent effects of the diterpenes and suggest caution in interpretation of cAMP effects on chromaffin cells when its cellular levels are modified by forskolin.
Gandía
L
L
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Canada.
Vitale
M L
ML
Villarroya
M
M
Ramirez-Lavergne
C
C
García
A G
AG
Trifaró
J M
JM
D000199:Actins / Q000037:antagonists & inhibitors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002395:Catecholamines / Q000037:antagonists & inhibitors; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018260:Gelsolin; D008564:Membrane Potentials / Q000187:drug effects; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors; D008856:Microscopy, Fluorescence; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology*
D000199:Actins; D002121:Calcium Channel Blockers; D002395:Catecholamines; D018260:Gelsolin; D008840:Microfilament Proteins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; C065395:scinderin; D005576:Colforsin; D009538:Nicotine; C047983:1,9-dideoxyforskolin; D011188:Potassium; D002118:Calcium