Mouse Hypothalamic Somatostatin Release: Roles of Calcium and Calmodulin*

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Abstract
A short term system of dispersed adult mouse hypothalamic cells, as previously described in the rat, was employed to examine the roles of Ca and calmodulin in SRIF [somatostatin] release. Incubation studies were performed 24 h after hypothalamic cell dispersion. SRIF release, as determined by RIA [radioimmunoassay] was stimulated in a dose-dependent manner by the membrane-depolarizing agents KCl, ouabain and veratridine as well as by the Ca ionophore A23187 [calcimycin]. The stimulation of SRIF release induced by depolarizing agents was abolished or diminished by omission of extracellular Ca, chelation of extracellular Ca by EGTA, the Ca channel blocker verapamil, indicating Ca dependence of this process. Three chemically distinct groups of calmodulin inhibitors were employed to study the role of calmodulin in stimulus-secretion coupling of hypothalamic SRIF. The neuroleptic calmodulin inhibitors trifluperazine (1 .mu.M), chlorpromazine (10 .mu.M) and promethazine (10 .mu.M) as well as the naphthalene sulfonamide calmodulin inhibitor Wt [N-(6-aminohexyl-5-chloro-1-naphthalene-sulfonamide)] (1 .mu.M) and compound 48/80 (50 .mu.g/ml) were all demonstrated to have an inhibitory effect on the sitmulation of SRIF release induced by membrane depolarization. No inhibitory effect of the less potent naphthalene sulfonamide agent W5 was observed at 1 .mu.M, although an inhibitory effect was seen at 10 .mu.M. The stimulation of SRIF release induced by A23187 was not inhibited by omission of extracelluar Ca or by verapamil, but was inhibited by EGTA [ethylene glycol bis(aminoethyl ether) N,N,N''N''-tetraacetic acid] and trifluperazine. The role of Ca in membrane depolarization-induced stimulus-secretion coupling of mouse hypothalamic SRIF was demonstrated. Inhibition of the stimulatory response by low concentrations of 3 distinct groups of calmodulin inhibitors, i.e., neuroleptics, naphthalenesulfonamide agents and compound 48/80, suggests a role for calmodulin in this process.

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