Kisspeptin inhibits a slow afterhyperpolarization current via protein kinase C and reduces spike frequency adaptation in GnRH neurons

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13 Scopus citations

Abstract

Kisspeptin signaling via its cognate receptor G protein-coupled receptor 54 (GPR54) in gonadotropin-releasing hormone (GnRH) neurons plays a critical role in regulating pituitary secretion of luteinizing hormone and thus reproductive function. GPR54 is Gq-coupled to activation of phos-pholipase C and multiple second messenger signaling pathways. Previous studies have shown that kisspeptin potently depolarizes GnRH neurons through the activation of canonical transient receptor potential channels and inhibition of inwardly rectifying K+ channels to generate sustained firing. Since the initial studies showing that kisspeptin has prolonged effects, the question has been why is there very little spike frequency adaption during sustained firing? Presently, we have discovered that kisspeptin reduces spike frequency adaptation and prolongs firing via the inhibition of a calcium-activated slow afterhyperpolarization current (I sahp). GnRH neurons expressed two distinct I sahp, a kisspeptin-sensitive and an apamin-sensitive I sahp. Essentially, kisspeptin inhibited 50% of the I sahp and apamin inhibited the other 50% of the current. Furthermore, the kisspeptin-medi-ated inhibition of I sahp was abrogated by the protein kinase C (PKC) inhibitor calphostin C, and the PKC activator phorbol 12,13-dibu-tyrate mimicked and occluded any further effects of kisspeptin on I sahp. The protein kinase A (PKA) inhibitors H-89 and the Rp diastereomer of adenosine 3',5'-cyclic monophosphorothioate had no effect on the kisspeptin-mediated inhibition but were able to abrogate the inhibitory effects of forskolin on the I sahp, suggesting that PKA is not involved. Therefore, in addition to increasing the firing rate through an overt depolarization, kisspeptin can also facilitate sustained firing through inhibiting an apamin-insensitive I sahp in GnRH neurons via a PKC.

Original languageEnglish (US)
Pages (from-to)E1237-E1244
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume304
Issue number11
DOIs
StatePublished - Jun 1 2013

Keywords

  • Apamin
  • Calcium-activated potassium current
  • Calcium-activated slow afterhyperpolarization current
  • Gonadotropin-releasing hormone

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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