Blockade of low and high threshold Ca2+ channels by diphenylbutylpiperidine antipsychotics linked to inhibition of prolactin gene expression

J. J. Enyeart, B. A. Biagi, R. N. Day, S. S. Sheu, R. A. Maurer

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

The effects of diphenylbutylpiperidine (DPBP) antipsychotics on Ca2+ currents and prolactin (PRL) synthesis were studied in rat pituitary growth hormone (GH) cell lines (GH3 and GH4C1). In whole-cell patch-clamp experiments, DPBPs including fluspirilene, penfluridol, and pimozide at concentrations ranging from 0.25 to 5 μM each blocked current through low threshold T-type as well as high threshold L-type channels. Each of the drugs preferentially blocked T-type current, and complete inhibition was observed at concentrations as low as 1 μM. Inhibition of L-type channels by DPBPS was enhanced at depolarized holding potentials and promoted by prolonged channel activation. At concentrations similar to those which blocked Ca2+ currents, each of the three DPBPs markedly reduced basal PRL production by GH cells. PRL synthesis stimulated by the dihydropyridine Ca2+ agonist R5417 or thyrotropin releasing hormone (TRH) was also inhibited. The inhibitory effects of the DPBPs were observed at the level of gene transcription. Penfluridol and fluspirilene inhibited basal, Ca2+- and TRH-stimulated expression of a fusion gene construct containing the 5'-flanking sequence of the rat PRL gene linked to the luciferase gene. The effect was concentration-dependent with the IC50 values for both drugs of less than 1 μM. Nimodipine also reduced basal, R5417, and TRH-stimulated expression of the reporter gene construct. Similar results were obtained with a reporter gene construct containing the 5'-flanking sequence of the rat GH gene. The GH luciferase construct was only slightly responsive to R5417 and TRH; however, these responses were reduced by fluspirilene and nimodipine at concentrations of less than 1 μM. These studies demonstrate that the DPBP antipsychotics block T- as well as L-type Ca2+ channels in GH cells and inhibit PRL production at the level of transcription. They also indicate that functioning Ca2+ channels are necessary for TRH-stimulated PRL gene transcription.

Original languageEnglish (US)
Pages (from-to)16373-16379
Number of pages7
JournalJournal of Biological Chemistry
Volume265
Issue number27
StatePublished - Oct 22 1990

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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