Essential role of G protein-gated inwardly rectifying potassium channels in gonadotropin-induced regulation of GnRH neuronal firing and pulsatile neurosecretion.
Activation of the luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor (LHR) in cultured hypothalamic cells and immortalized GnRH (gonadotropin-releasing hormone) neurons (GT1-7 cells) transiently stimulates and subsequently inhibits cAMP production and pulsatile GnRH release. The marked and delayed impairment of cAMP signaling and episodic GnRH release in GT1-7 cells is prevented by pertussis toxin (PTX). This, and the LH-induced release of membrane-bound Galpha(s) and Galpha(i3) subunits, are indicative of differential G protein coupling to the LHR. Action potential (AP) firing in identified GnRH neurons also initially increased and then progressively decreased during LH treatment. The inhibitory action of LH on AP firing was also prevented by PTX. Reverse transcriptase-PCR analysis of GT1-7 neurons revealed the expression of G protein-gated inwardly rectifying potassium (GIRK) channels in these cells. The LH-induced currents were inhibited by PTX and were identified as GIRK currents. These responses indicate that agonist stimulation of endogenous LHR expressed in GnRH neurons activates GIRK channels, leading to suppression of membrane excitability and inhibition of AP firing. These findings demonstrate that regulation of GIRK channel function is a dominant factor in gonadotropin-induced abolition of pulsatile GnRH release. Furthermore, this mechanism could contribute to the suppression of pituitary function during pregnancy.
Hu
Lian
L
Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-4510, USA.
Wada
Keiko
K
Mores
Nadia
N
Krsmanovic
Lazar Z
LZ
Catt
Kevin J
KJ
D000200:Action Potentials; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry*; D007986:Luteinizing Hormone / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D037342:Pertussis Toxin / Q000378:metabolism; D011188:Potassium / Q000737:chemistry; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011188:Potassium