PT  - JOURNAL ARTICLE
AU  - Chunguang Zhang
AU  - Troy A. Roepke
AU  - Martin J. Kelly
AU  - Oline K. Rønnekleiv
TI  - Kisspeptin Depolarizes Gonadotropin-Releasing Hormone Neurons through Activation of TRPC-Like Cationic Channels
AID  - 10.1523/JNEUROSCI.5352-07.2008
DP  - 2008 Apr 23
TA  - The Journal of Neuroscience
PG  - 4423--4434
VI  - 28
IP  - 17
4099  - http://www.jneurosci.org/content/28/17/4423.short
4100  - http://www.jneurosci.org/content/28/17/4423.full
SO  - J. Neurosci.2008 Apr 23; 28
AB  - 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 EK+ (−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 5 mm) 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.