Rapid regulation of K(ATP) channel activity by 17{beta}-estradiol in pancreatic {beta}-cells involves the estrogen receptor {beta} and the atrial natriuretic peptide receptor

Mol Endocrinol. 2009 Dec;23(12):1973-82. doi: 10.1210/me.2009-0287. Epub 2009 Oct 23.

Abstract

The ATP-sensitive potassium (K(ATP)) channel is a key molecule involved in glucose-stimulated insulin secretion. The activity of this channel regulates beta-cell membrane potential, glucose- induced [Ca(2+)](i) signals, and insulin release. In this study, the rapid effect of physiological concentrations of 17beta-estradiol (E2) on K(ATP) 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 K(ATP) channel activity by 60%. The action of E2 on K(ATP) channel was not modified in beta-cells from ERalpha-/- mice, yet it was significantly reduced in cells from ERbeta-/- mice. The effect of E2 was mimicked by the ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). Activation of ERbeta by DPN enhanced glucose-induced Ca(2+) signals and insulin release. Previous evidence indicated that the acute inhibitory effects of E2 on K(ATP) 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 K(ATP) channel activity and enhanced insulin release in islets from WT mice but not in islets from GC-A KO mice. In addition, DPN reduced K(ATP) 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 ERbeta as an insulinotropic molecule that may have important physiological and pharmacological implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / agonists
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / physiology
  • Estrogen Receptor beta / agonists
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / physiology*
  • Female
  • Immunohistochemistry
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism*
  • KATP Channels / drug effects*
  • KATP Channels / metabolism*
  • Mice
  • Mice, Knockout
  • Nitriles / pharmacology
  • Patch-Clamp Techniques
  • Phenols
  • Pyrazoles / pharmacology
  • Receptors, Atrial Natriuretic Factor / genetics
  • Receptors, Atrial Natriuretic Factor / physiology*

Substances

  • 2,3-bis(4-hydroxyphenyl)-propionitrile
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • KATP Channels
  • Nitriles
  • Phenols
  • Pyrazoles
  • 4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
  • Estradiol
  • Receptors, Atrial Natriuretic Factor
  • Calcium