title: Dehydroepiandrosterone inhibits intracellular calcium release in beta-cells by a plasma membrane-dependent mechanism.
abstract: Both dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) affect glucose stimulated insulin secretion, though their cellular mechanisms of action are not well characterized. We tested the hypothesis that human physiological concentrations of DHEA alter insulin secretion by an action initiated at the plasma membrane of beta-cells. DHEA alone had no effect on intracellular calcium concentration ([Ca(2+)](i)) in a rat beta-cell line (INS-1). However, it caused an immediate and dose-dependent inhibition of carbachol-induced Ca(2+) release from intracellular stores, with a 25% inhibition at zero. One nanometer DHEA. DHEA also inhibited the Ca(2+) mobilizing effect of bombesin (29% decrease), but did not inhibit the influx of extracellular Ca(2+) evoked by glyburide (100 microM) or glucose (15 mM). The steroids (androstenedione, 17-alpha-hydroxypregnenolone, and DHEAS) had no inhibitory effect on carbachol-induced intracellular Ca(2+) release. The action of DHEA depended on a signal initiated at the plasma membrane, since membrane impermeant DHEA-BSA complexes also inhibited the carbachol effect on [Ca(2+)](i) (39% decrease). The inhibition of carbachol-induced Ca(2+) release by DHEA was blocked by pertussis toxin (PTX). DHEA also inhibited the carbachol induction of phosphoinositide generation, with a maximal inhibition at 0.1 nM DHEA. Furthermore, DHEA inhibited insulin secretion induced by carbachol in INS-1 cells by 25%, and in human pancreatic islets by 53%. Taken together, this is the first report showing that human physiological concentrations of DHEA decrease agonist-induced Ca(2+) release by a rapid, non-genomic mechanism in INS-1 cells. Furthermore, these data provide evidence consistent with the existence of a specific plasma membrane DHEA receptor, mediating this signal transduction pathway by pertussis toxin-sensitive G-proteins.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, 52242, USA.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Ren
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bing
authors.forename: Corey
authors.initials: C
authors.lastname: Stotts
authors.forename: Sundeep
authors.initials: S
authors.lastname: Deorah
authors.forename: Laurie
authors.initials: L
authors.lastname: Love-Homan
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Dillon
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D052139:Intracellular Calcium-Sensing Proteins / Q000378:metabolism; D051381:Rats; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D007328:Insulin; D052139:Intracellular Calcium-Sensing Proteins; D003687:Dehydroepiandrosterone; D002217:Carbachol; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium