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.
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.
Soriano
Sergi
S
Institute of Bioengineering and CIBERDEM, Universidad Miguel Hernández de Elche, Alicante, Spain.
Ropero
Ana B
AB
Alonso-Magdalena
Paloma
P
Ripoll
Cristina
C
Quesada
Ivan
I
Gassner
Birgit
B
Kuhn
Michaela
M
Gustafsson
Jan-Ake
JA
Nadal
Angel
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000502:physiology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D054086:KATP Channels / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010636:Phenols; D011720:Pyrazoles / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000502:physiology*; D011422:Propionates
D002118:Calcium; D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D054086:KATP Channels; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; D017461:Receptors, Atrial Natriuretic Factor; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol