Mechanisms of action of inhibitors of prolactin secretion in GH3 pituitary cells. II. Blockade of voltage-dependent Ca2+ channels

SE Wolfe and MA Brostrom

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.

Volume 29, Issue 4, pp. 420-426, 04/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics