Mechanisms of action of inhibitors of prolactin secretion in GH3 pituitary cells. II. Blockade of voltage-dependent Ca2+ channels.
Pharmacologic agents reported to inhibit prolactin secretion by GH3 pituitary cells were observed to inhibit protein synthesis by these cells in a Ca2+-dependent manner. The possibility that these substances exert their effects on protein synthesis by restricting intracellular Ca2+ availability was explored. Trifluoperazine and chlorpromazine at concentrations that inhibit amino acid incorporation reduced uptake of 45Ca2+ by intact cells approximately 30% under nondepolarizing conditions. Increased extracellular K+ (30 mM), which depolarizes the membrane and opens the voltage-dependent Ca2+ channel of GH3 cells, produced a 2-fold increase in 45Ca2+ uptake; phenothiazines fully suppressed this effect of K+. Nifedipine, verapamil, ergotamine, bromocriptine, (+)- and (-)-butaclamol, and calmidazolium were also effective in inhibiting 45Ca2+ uptake under depolarizing and nondepolarizing conditions. The membrane potential of either depolarized or nondepolarized cells, as determined by [3H]tetraphenylphosphonium+ distribution, was not affected significantly by secretory inhibitors. Increased extracellular K+ altered protein synthesis by GH3 cells in a biphasic manner. Amino acid incorporation by cells incubated at low extracellular Ca2+ concentrations was stimulated by K+, whereas incorporation by cells in high Ca2+ medium was inhibited by K+. Trifluoperazine, chlorpromazine, nifedipine, and bromocriptine suppressed both effects of K+ on protein synthesis. It is proposed that these antagonists of secretion inhibit protein synthesis by GH3 cells through blockade of voltage-dependent Ca2+ channels.
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D000200:Action Potentials / Q000187:drug effects; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002746:Chlorpromazine / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D009861:Onium Compounds / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D014268:Trifluoperazine / Q000494:pharmacology
D000596:Amino Acids; D007473:Ion Channels; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D014268:Trifluoperazine; D011388:Prolactin; D011188:Potassium; D002118:Calcium; D002746:Chlorpromazine; C013289:tetraphenylphosphonium