Ca++ antagonists distinguish different requirements for cAMP-mediated gene expression in the cellular slime mold, Dictyostelium discoideum.
Cyclic AMP is essential for the accumulation of many prespore mRNAs and can advance the time of appearance of mRNAs specifically enriched in prestalk cells. Additionally, when late-developing cells are washed free of cAMP, a number of growth phase mRNAs reaccumulate. This reaccumulation can be suppressed by cAMP. These effects of cAMP are all mediated through the cell surface cAMP receptor and can occur under conditions where the receptor-associated adenylate cyclase is inactive, indicating that the initial intracellular transduction event necessary for expression of these mRNAs does not depend upon cAMP synthesis. The dihydropyridine derivatives, nifedipine and nitrendipine, are highly specific Ca++ channel blockers. They are shown here to prevent the influx of Ca++ from the external medium that occurs in response to cAMP binding to the cell surface receptor during development. These two compounds as well as another Ca++ antagonist, 8-N,N-diethylamino)octyl-3,4,5-trimethoxy-benzoate (TMB-8) and a calmodulin inhibitor, N-(6-amino-hexyl)-5-chloro-1-naphthalene sulfonamide (W7), all specifically decrease cAMP-mediated prespore mRNA accumulation in a dose-dependent manner. They also prevent cAMP from suppressing the expression of the growth phase genes. The growth phase mRNAs reaccumulate in cAMP-treated cells in the presence of increasing concentrations of these drugs. By contrast, cAMP induction of the pre-stalk-enriched mRNA is not as significantly affected by these agents. These results raise the possibility that the cell surface cAMP receptor can couple to different signal transduction systems and thereby induce or suppress the expression of different sets of cAMP-regulated genes during development.
Blumberg
D D
DD
Department of Biological Sciences, University of Maryland Baltimore County, Catonsville 21228.
Comer
J F
JF
Walton
E M
EM
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D000242:Cyclic AMP / Q000494:pharmacology*; D004023:Dictyostelium / Q000166:cytology / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology; D005707:Gallic Acid / Q000494:pharmacology / Q000031:analogs & derivatives; D015870:Gene Expression / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002147:Calmodulin; D004095:Dihydropyridines; D012333:RNA, Messenger; D013449:Sulfonamides; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; C017967:W 7; D000242:Cyclic AMP