17β-estradiol rapidly increases KATP activity in GnRH via a protein kinase signaling pathway

Chunguang Zhang, Martin Kelly, Oline Ronnekleiv

Research output: Contribution to journalArticle

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Abstract

17β-Estradiol (E2) both inhibits and excites GnRH neurons via presynaptic as well as postsynaptic mechanisms. Although it has been demonstrated that E2 can alter the excitability of GnRH neurons via direct actions, the intracellular signaling cascades mediating these actions are not well understood. Previously we have shown that the activity of one of the critical ion channels needed for maintaining GnRH neurons in a hyperpolarized state, the ATP-sensitive potassium channel (KATP) channel, is augmented by E2 in ovariectomized females. However, the mRNA expression of the KATP channel subunits Kir6.2 and SUR1 are unchanged with in vivo E2 treatment. Therefore, to elucidate the cellular signaling mechanism(s) modulating the channel activity, we did whole-cell patch-clamp recording of enhanced green fluorescent protein-GnRH neurons from ovariectomized female mice to study the acute effects of E2. E2 dose-dependently (EC50 = 0.6 nM) enhanced the diazoxide (channel opener)-activated KATP channel currents by 1.2- to 2.0-fold, which was antagonized by ICI 182,780. E2-BSA was equally as effective as E2, whereas E2 had no effect. The protein kinase A (PKA) activator forskolin mimicked the effects of E2, whereas the PKA inhibitor H89 and the protein kinase C (PKC) inhibitor bisindolylmaleimide I blocked the effects of E2. Similar to E2, STX, a membrane estrogen receptor (ER) agonist that does not bind to ERα or ERβ, also potentiated the diazoxide-induced KATP channel current by 1.5-fold. Therefore, E2 can potentiate KATP channel activity in GnRH neurons through a membrane ER-activated PKC-PKA signaling pathway.

Original languageEnglish (US)
Pages (from-to)4477-4484
Number of pages8
JournalEndocrinology
Volume151
Issue number9
DOIs
StatePublished - Sep 2010

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KATP Channels
Gonadotropin-Releasing Hormone
Protein Kinases
Estradiol
Neurons
Cyclic AMP-Dependent Protein Kinases
Diazoxide
Protein Kinase Inhibitors
Estrogen Receptors
Membranes
Protein C Inhibitor
Colforsin
Ion Channels
Protein Kinase C
Estrogens
Messenger RNA

ASJC Scopus subject areas

  • Endocrinology

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17β-estradiol rapidly increases KATP activity in GnRH via a protein kinase signaling pathway. / Zhang, Chunguang; Kelly, Martin; Ronnekleiv, Oline.

In: Endocrinology, Vol. 151, No. 9, 09.2010, p. 4477-4484.

Research output: Contribution to journalArticle

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