Thyrotropin-Releasing Hormone Rapidly Stimulates a Biphasic Secretion of Prolactin and Growth Hormone in GH4C1Rat Pituitary Tumor Cells*

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Abstract
The characteristics of TRH-induced acute PRL [prolactin] and GH [growth hormone] secretion were studied in GH4C1 cells, a cloned rat anterior pituitary tumor cell line which secretes PRL and GH. The experiments were carried out both in a flow system in which microcarrier (Cytodex)-attached cells were perifused at a constant rate and in a conventional static culture system. In both systems, cells responded to TRH in a qualitatively similar manner. TRH significantly stimulated PRL and GH secretion within 5 s without a detectable lag period. The secretion rate was highest during the initial 1 min, declined sharply thereafter despite the continuous presence of TRH, and plateaued at a lower level. The maximum dose of TRH caused 250-700% of basal secretion during the early period (.apprx. 8 min; 1st phase) and .apprx. 150% of basal secretion thereafter (2nd phase). The sustained lower secretion (2nd phase) was maintained as long as cells were exposed to TRH (up to 2.5 h), and the secretion rate returned to the basal level within 30 min of removal of TRH from the medium. The half-maximal doses for the 1st and 2nd phase secretion were 2-3 and 0.5-1 nM, respectively, in both the perfusion and static culture systems. Over a 2-day period, TRH stimulated PRL synthesis and inhibited GH synthesis. The dose-response curves for these long term effects on hormone synthesis were similar to the dose-response curves for the 1st phase of release. [N3-methyl-His2]TRH gave similar results, but was more potent than TRH. [N3-methyl-His2]TRH stimulated 1st phase release with an ED50 of 0.4-0.8 nM, 2nd phase release with an ED50 of 0.1-0.2 nM, and hormone synthesis with an ED50 of 0.7-0.8 nM. Preincubation of the cells with Ca2+-free medium significantly depressed both 1st and 2nd phase secretion. Preexposure of the cells to cycloheximide (10 .mu.g/ml) had little effect on the 1st phase of secretion, but reduced 2nd phase secretion. The acute effects of TRH on GH and PRL were identical, except that the secretory response tended to be greater for PRL. TRH causes hormone secretion very rapidly in biphasic manner. The 1st phase of secretion consists primarily of the release of stored hormone; the 2nd phase includes the release of newly synthesized hormone. The dose-response curve of 2nd phase secretion is shifted to the left compared with that of 1st phase secretion. Both phases of secretion are at least partially dependent on extracellular Ca2+.

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