title: The involvement of dihydropyridine-sensitive calcium channels in phorbol ester-induced luteinizing hormone and growth hormone release.
abstract: We examined the role of voltage-activated, L-type, Ca2+ channels in phorbol ester-induced luteinizing hormone (LH) and growth hormone (GH) release from rat anterior pituitary tissue. The L-type Ca2+ channel inhibitor, nimodipine (NMD), inhibited phorbol 12,13-dibutyrate (PDBu)-induced GH release but had no significant effect on LH release. The L-type Ca2+ channel activator BAY K 8644 had no effect on PDBu-induced GH release but potentiated PDBu-induced LH release. In contrast, 60 mM K(+)-induced LH and GH release were inhibited by NMD, whereas BAY K 8644 had no effect. When PDBu and either K+ or BAY K 8644 were used together, they acted synergistically to evoke levels of LH release greater than addition of release caused by each secretagogue alone. However, the release of GH was additive with PDBu and either K+, BAY K 8644. The protein kinase C (PKC) inhibitor staurosporine inhibited both PDBu-induced LH release and GH release. A structurally different PKC inhibitor, H7, significantly inhibited PDBu-induced LH release but had no effect on PDBu-induced GH release. Both staurosporine and H7 inhibited LH release induced by PDBu and BAY K 8644 together. In contrast, although staurosporine inhibited GH release induced by PDBu and BAY K 8644, H7 significantly potentiated this response. A difference in the action of these two inhibitors was also apparent on K(+)-induced hormone release where staurosporine partially blocked K(+)-induced LH and GH release but H7 had no effect on the release of either hormone. Data obtained in 45Ca2+ influx experiments further suggested that a staurosporine-sensitive, but H7-resistant, PKC-like kinase may tonically maintain L-channels in a voltage-sensitive state, as down-regulation of PKC in dispersed anterior pituitary cells by long term PDBu treatment caused a significant reduction in K(+)-induced 45Ca2+ influx. We conclude that phorbol ester-induced GH release, but not LH release, is a result of L-type Ca2+ channel activation which may occur by means of alterations in the channel itself to increase its responsiveness to a given depolarisation.
authors.affiliation: MRC Brain Metabolism Unit, University Department of Pharmacology, Edinburgh, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Johnson
authors.forename: F J
authors.initials: FJ
authors.lastname: Thomson
authors.forename: D J
authors.initials: DJ
authors.lastname: MacEwan
authors.forename: R
authors.initials: R
authors.lastname: Mitchell
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019311:Staurosporine
chemical_list: D000470:Alkaloids; D015220:Calcium Channels; D004095:Dihydropyridines; D007546:Isoquinolines; D010879:Piperazines; D015240:Phorbol 12,13-Dibutyrate; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C038806:1,4-dihydropyridine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D007986:Luteinizing Hormone; D013006:Growth Hormone; D011493:Protein Kinase C; D019311:Staurosporine; D002118:Calcium