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

John J. Enyeart, Bruce A. Biagi, Richard Day, Shey Shing Sheu, Richard A. Maurer

Research output: Contribution to journalArticle

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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 - Sep 25 1990
Externally publishedYes

Fingerprint

Thyrotropin-Releasing Hormone
Gene expression
Prolactin
Antipsychotic Agents
Fluspirilene
Genes
Growth Hormone
Gene Expression
Penfluridol
Nimodipine
Transcription
5' Flanking Region
Luciferases
Reporter Genes
Rats
Pimozide
Gene Fusion
Pharmaceutical Preparations
Inhibitory Concentration 50
Clamping devices

ASJC Scopus subject areas

  • Biochemistry

Cite this

Blockade of low and high threshold Ca2+ channels by diphenylbutylpiperidine antipsychotics linked to inhibition of prolactin gene expression. / Enyeart, John J.; Biagi, Bruce A.; Day, Richard; Sheu, Shey Shing; Maurer, Richard A.

In: Journal of Biological Chemistry, Vol. 265, No. 27, 25.09.1990, p. 16373-16379.

Research output: Contribution to journalArticle

Enyeart, John J. ; Biagi, Bruce A. ; Day, Richard ; Sheu, Shey Shing ; Maurer, Richard A. / Blockade of low and high threshold Ca2+ channels by diphenylbutylpiperidine antipsychotics linked to inhibition of prolactin gene expression. In: Journal of Biological Chemistry. 1990 ; Vol. 265, No. 27. pp. 16373-16379.
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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.",
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