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

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 [Ca2+](i) signals, and insulin release. In this study, the rapid effect of physiological concentrations of 17 beta-estradiol (E2) on K-ATP channel activity was studied in intact beta-cells by use of the patch-clamp technique. Whencells 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 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(4hydroxyphenyl)-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 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 ER beta as an insulinotropic molecule that may have important physiological and pharmacological implications. (Molecular Endocrinology 23: 1973-1982, 2009)