DIFFERENTIAL MECHANISMS OF DOPAMINE AND SOMATOSTATIN INHIBITION OF PROLACTIN SECRETION FROM ANTERIOR-PITUITARY-CELLS

The relative potencies of dopamine and somatostatin to inhibit prolactin secretion by pituitary cells in primary culture were compared. Hormone secretion was evaluated under basal conditions as well as after challenging it with thyrotropin-releasing hormone, vasoactive intestinal peptide or with drugs affecting either the activity of adenylate cyclase (forskolin), and protein kinase C (phorbol 12 myristate 13 acetate), or eliciting Ca2+ fluxes in the cell by various ways (A23187, a Ca2+ ionophore, the dihydropyridine agonist BAY-K-8644, or K+ depolarization which activates voltage-sensitive Ca2+ channels). In order to test whether all effects of dopamine and somatostatin were mediated by inhibitory guanosine triphosphate binding proteins, the experiments were systematically carried out in the presence or absence of pertussis toxin, an agent which selectively uncouples given subsets of G proteins from corresponding receptors. Dopamine markedly inhibited basal as well as thyrotropin-releasing hormone-, vasoactive intestinal peptide-, forskolin- and BAY-K-8644-stimulated release of prolactin. In contrast, dopamine was only able to induce partial inhibition of hormone release when secretion was triggered by tumor-promoting activator, A23187 or K+ depolarization. Under all conditions tested, inhibition by somatostatin was significant, but of limited amplitude. Pertussis toxin completely reversed the effects of somatostatin. In contrast, complete reversal of dopamine effects by pertussis toxin was only achieved after hormone stimulation by tumor-promoting activator, alone or with A23187. Under all other conditions a residual dopamine inhibition was maintained in the presence of the toxin. The amplitude of this residual toxin resistant inhibition was comparable in all other cases to that observed for unstimulated (basal) prolactin release. It is concluded that: 1) As expected, dopamine is a potent inhibitor of secretory processes involving cyclic AMP accumulation or voltage-sensitive Ca2+ channel activation. In contrast, the amine is only a partial inhibitor of exocytosis resulting from non-voltage-sensitive Ca2+ channel-gated increase in Ca2+ or direct activation of protein kinase C. 2) Somatostatin is a partial inhibitor of prolactin under all conditions tested. Dopamine and all somatostatin effects are mediated by pertussis toxin-sensitive G proteins. However, a small, but significant, proportion of dopamine inhibition is resistant to pertussis toxin and can thus be assumed to involve a distinct mode of action. This alternate mechanism of dopamine inhibition operates under all conditions except after treatment with tumour-promoting activator, suggesting that it can be inactivated by protein kinase C stimulation.