Opposing Actions of Bay K 8644 Enantiomers on Calcium Current, Prolactin Secretion, and Synthesis in Pituitary Cells

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Abstract
Dihydropyridine (DHP) Ca2+ channel modulators were used to explore the relationship between voltage-gated Ca2+ channels and PRL secretion, synthesis and mRNA in PRL-secreting pituitary cells. Optical isomers of the Ca2+ channel agonist Bay K 8644 produced stereospecific and opposing effects on L-type Ca2+ current, PRL release, and synthesis in GH3 and GH4C1 cells. (-)-Bay K 8644 (R5417) behaved as a pure agonist, enhancing Ca2+ current several-fold while shifting the current-voltage curve 10-15 mV in the hyperpolarizing direction. The agonist effect was independent of holding potential, but decreased during prolonged Ba2+ or Ca2+ entry. R5417 produced a concentration-dependent increase in acute PRL release and enhanced PRL production by GH cells several-fold during a 72-h period. (+)-Bay K 8644(R4407) behaved as a weak Ca2+ channel antagonist, inhibiting L-type Ca2+ current, KCl-stimulated PRL secretion, and PRL production at concentrations of 0.5-5 .mu.M. These two isomers produced similar effects on PRL production by normal rat pituitary cells in dispersed culture. R5417 (500 nM) increased PRL produced in 72 h to 233 .+-. 8% of the control value. R4407 reduced this quantity by 36 .+-. 9%. The effects of the DHPs on PRL mRNA levels were consistent with the effects observed for acute secretion and hormone production. The agonist R5417 increased PRL mRNA 147 .+-. 5% over a 30-h period, and the potent DHP Ca2+ channel blocker nimodipine inhibited PRL mRNA production 2-fold. These results demonstrate that racemic Bay K8644 interacts with L-type Ca2+ channels in normal and transformed pituitary cells as a mixed agonist-antagonist. Modulation of Ca2+ channels at the plasma membrane by the separate isomers and nimodipine is linked to the regulation of PRL synthesis at the level of transcription. It is suggested that spontaneous and modulated electrical activity in pituitary cells may be coupled to hormone synthesis through voltage-gated Ca2+ channels.