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Growth Hormone-Releasing Factor Secretion from Fetal Hypothalamic Cell Cultures Is Modulated by Forskolin, Phorbol Esters, and Muscimol^*

MYRIAM BAES and WYLIE W. VALE

The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute La Jolla, California 92037

Address requests for reprints to: Dr. Myriam Baes, Laboratory of Cell Pharmacology, University of Leuven, Campus Gasthuisberg (O and N), Herestraat 49, B-3000 Leuven, Belgium.

Abstract

The regulation of GRF secretion was studied using a fetal rat hypothalamic cell culture system. The cells were subjected to short term release experiments on days 10–18 after plating, and GRF secretion was assessed by RIA. The identity of GRF immunoreactivity in the incubation medium was confirmed by reverse phase liquid chromatographic analysis. Depolarization of the cells with 56 mM K⁺ evoked a 4-fold increase in basal GRF release. When cultures were pretreated for 6 days with the adenylate cyclase activator forskolin, basal GRF release was augmented in subsequent release experiments to levels 2- fold greater than those in the control cultures. In nonpretreated cultures, forskolin (1-100µM) and the protein kinase C activator phorbol 12-myristate 13-acetate (10 nM-1 µM),stimulated basal GRF release in a dose-dependent fashion. The Ca²⁺ channel blocker verapamil (100 nM) significantly inhibited the GRF response to both forskolin and phorbol 12-myristate 13-acetate. The -aminobutyric acid (GABA) agonist muscimol (0.1–10 µM) inhibited forskolin-stimulated, but not K⁺ stimulated, GRF release in a dose-dependent manner. This inhibition was reversed by the GABA antagonists bicuculline and picrotoxinin. Muscimol (10 µM) slightly suppressed basal GRF release. The present findings suggest that GRF secretion can be evoked by agents known to increase intracellular cAMP levels or activate protein kinase-C. They also support a role for GABA in the inhibitory control of GRF secretion. (Endocrinology 124: 104–110,1989)

Footnotes

^* This work was supported by NIH Grant DK-26741 and was conducted in part by the Clayton Foundation for Research, California Division.

Recipient of a fellowship from the Belgian National Science Foundation.

Received July 13, 1988.

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