17 β-estradiol rapidly increases ATP-sensitive potassium channel activity in gonadotropin-releasing hormone neurons [corrected] via a protein kinase signaling pathway.
17Beta-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 (K(ATP)) channel, is augmented by E2 in ovariectomized females. However, the mRNA expression of the K(ATP) 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 (EC(50) = 0.6 nM) enhanced the diazoxide (channel opener)-activated K(ATP) 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 17 alpha-estradiol [corrected] 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 ERalpha or ERbeta, also potentiated the diazoxide-induced K(ATP) channel current by 1.5-fold. Therefore, E2 can potentiate K(ATP) channel activity in GnRH neurons through a membrane ER-activated PKC-PKA signaling pathway.
Zhang
Chunguang
C
Department of Physiology and Pharmacology, Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon 97239-3089, USA.
Kelly
Martin J
MJ
Rønnekleiv
Oline K
OK
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D011301:Preoptic Area / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D004965:Estrogen Antagonists; D015221:Potassium Channels; D011960:Receptors, Estrogen; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D049452:Green Fluorescent Proteins; D000077267:Fulvestrant; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D003981:Diazoxide