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This version published online on October 23, 2009
Molecular Endocrinology, doi:10.1210/me.2009-0287
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Submitted on July 21, 2009
Accepted on September 3, 2009

Rapid Regulation of KATP Channel Activity by 17{beta}-Estradiol in Pancreatic {beta}-Cells Involves the Estrogen Receptor {beta} and the Atrial Natriuretic Peptide Receptor

Sergi Soriano, Ana B. Ropero, Paloma Alonso-Magdalena, Cristina Ripoll, Ivan Quesada, Birgit Gassner, Michaela Kuhn, Jan-Åke Gustafsson, and Angel Nadal*

Instituto de Bioingeniería and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM (S.S., A.B.R., P.A.-M., C.R., I.Q., A.N.), Universidad Miguel Hernández de Elche, 03202 Elche, Alicante, Spain; Institute of Physiology (B.G., M.K.), University of Würzburg, 97070 Wurzburg, Germany; Department of Biosciences and Nutrition (J.-A.G.), Karolinska Institute, Novum, Huddinge SE-141 57, Sweden; and Department of Cell Biology and Biochemistry (J.-A.G.), Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas 77204

* To whom correspondence should be addressed. E-mail: nadal{at}umh.es.

The ATP-sensitive potassium (KATP) channel is a key molecule involved in glucose-stimulated insulin secretion. The activity of this channel regulates {beta}-cell membrane potential, glucose- induced [Ca2+]i signals, and insulin release. In this study, the rapid effect of physiological concentrations of 17{beta}-estradiol (E2) on KATP channel activity was studied in intact {beta}-cells by use of the patch-clamp technique. When cells from wild-type (WT) mice were used, 1 nM E2 rapidly reduced KATP channel activity by 60%. The action of E2 on KATP channel was not modified in {beta}-cells from ER{alpha}-/- mice, yet it was significantly reduced in cells from ER{beta}-/- mice. The effect of E2 was mimicked by the ER{beta} agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). Activation of ER{beta} by DPN enhanced glucose-induced Ca2+ signals and insulin release. Previous evidence indicated that the acute inhibitory effects of E2 on KATP channel activity involve cyclic GMP and cyclic GMP-dependent protein kinase. In this study, we used {beta}-cells from mice with genetic ablation of the membrane guanylate cyclase A receptor for atrial natriuretic peptide (also called the atrial natriuretic peptide receptor) (GC-A KO mice) to demonstrate the involvement of this membrane receptor in the rapid E2 actions triggered in {beta}-cells. E2 rapidly inhibited KATP channel activity and enhanced insulin release in islets from WT mice but not in islets from GC-A KO mice. In addition, DPN reduced KATP channel activity in {beta}-cells from WT mice, but not in {beta}-cells from GC-A KO mice. This work unveils a new role for ER{beta} as an insulinotropic molecule that may have important physiological and pharmacological implications.

NURSA Molecule Pages Link:

Nuclear Receptors:   ER-β
Ligands:   17β-estradiol





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