Phorbol Ester and Phospholipase C-Induced Growth Hormone Secretion from Pituitary Somatotroph Adenoma Cells in Culture: Effects of Somatostatin, Bromocriptine, and Pertussis Toxin*

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Abstract
To clarify the role of the breakdown ofphosphatidylinositol 4,5-bisphosphate (PIP2) in GH secretion in human somatotrophs and the efffects of inhibitors of GH secretion on this mechanism, we studied the effects of 12-tetradecanoylphorbol-13-acetate (TPA) and phospholipase C (Plase C) on GH secretion and the interactions of somatostatin (SRIH), bromocriptine, and pertussis toxin (IAP) with TPA or Plase C, using human GH-secreting pituitary adenoma cells in culture. SRIH (10−9–10−7 M) inhibited and TPA (10−10–10−7 and Plase C (0.125–1.0 U/mL) stimulated GH secretion. SRIH (10−9−10−7 M) inhibited GH release induced by TPA (10−8 M) or Plase C (1.0 U/mL). Bromocriptine (10−8 M) also inhibited 10−8 M TPAinduced GH secretion. When adenoma cells were treated with 100 ng/mL IAP for 24 h, basal and TPA-induced GH secretion rates did not change. However, the inhibitory effects of SRIH (10−8 M) or bromocriptine (10−8 M) on basal and 10−8 M TPAstimulated GH secretion were attenuated. In addition, IAP reduced GH secretion induced by 0.5 U/mL Plase C, while SRIH inhibition of Plase C-evoked GH release was diminished by IAP. We conclude that 1) the hydrolysis of PIP2 by Plase C, which causes activation of protein kinase C by 1,2-diacylglycerol and Ca2+ mobilization by inositol 1,4,5-triphosphate, is a physiological intracellular mechanism leading to GH secretion in human somatotrophs; 2) SRIH inhibits GH secretion mediated by this mechanism, and bromocriptine blocks at least protein kinase Cmediated GH release; 3) the inhibitory guanine nucleotidebinding protein (Ni) is involved in these inhibitory effects of SRIH and bromocriptine; and 4) Ni modulates the breakdown of PIP2 by Plase C.

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