Kisspeptin depolarizes gonadotropin-releasing hormone neurons through activation of TRPC-like cationic channels

Chunguang Zhang, Troy A. Roepke, Martin J. Kelly, Oline K. Rønnekleiv

Research output: Contribution to journalArticle

164 Scopus citations

Abstract

Kisspeptin and its cognate receptor, GPR54, are critical for reproductive development and for the regulation of gonadotropin-releasing hormone (GnRH) secretion. Although kisspeptin has been found to depolarize GnRH neurons, the underlying ionic mechanism has not been elucidated. Presently, we found that kisspeptin depolarized GnRH neurons in a concentration-dependent manner with a maximum depolarization of 22.6 ± 0.6 mV and EC50 of 2.8 ± 0.2 nM. Under voltage-clamp conditions, kisspeptin induced an inward current of 18.2 ± 1.6 pA (Vhold = -60 mV) that reversed near -115 mV in GnRH neurons. The more negative reversal potential than E K+ (-90 mV)was caused by the concurrent inhibition of barium-sensitive, inwardly rectifying (Kir) potassium channels and activation of sodium-dependent, nonselective cationic channels (NSCCs). Indeed, reducing extracellular Na+ (to 5mM) essentially eliminated the kisspeptin-induced inward current. The current-voltage relationships of the kisspeptin-activated NSCC currents exhibited double rectification with negative slope conductance below -40 mV in the majority of the cells. Pharmacological examination showed that the kisspeptin-induced inward currents were blocked by TRPC (canonical transient receptor potential) channel blockers 2-APB (2-aminoethyl diphenylborinate), flufenamic acid, SKF96365 (1-[β-[3-(4- methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride), and Cd2+, but not by lanthanum (100 μM). Furthermore, single-cell reverse transcription-PCR analysis revealed that TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7 subunits were expressed in GnRH neurons. Therefore, it appears that kisspeptin depolarizes GnRH neurons through activating TRPC-like channels and, to a lesser extent, inhibition of Kir channels. These actions of kisspeptin contribute to the pronounced excitation of GnRH neurons that is critical for mammalian reproduction.

Original languageEnglish (US)
Pages (from-to)4423-4434
Number of pages12
JournalJournal of Neuroscience
Volume28
Issue number17
DOIs
StatePublished - Apr 23 2008

    Fingerprint

Keywords

  • Diacylglycerol
  • GPR54
  • Kir channels
  • Nonselective cationic channels
  • Phospholipase C
  • Single-cell RT-PCR

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this