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The Journal of Neuroscience, April 23, 2008, 28(17):4423-4434; doi:10.1523/JNEUROSCI.5352-07.2008

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Cellular/Molecular
Kisspeptin Depolarizes Gonadotropin-Releasing Hormone Neurons through Activation of TRPC-Like Cationic Channels

Chunguang Zhang,¹ Troy A. Roepke,¹ Martin J. Kelly,¹ and Oline K. Rønnekleiv^1,2,3

Departments of ¹Physiology and Pharmacology and ²Anesthesiology and Perioperative Medicine, and ³Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon 97239-3089

Correspondence should be addressed to either Dr. Martin J. Kelly or Dr. Oline K. Rønnekleiv, Department of Physiology and Pharmacology, L334, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-2098. Email: kellym{at}ohsu.edu or Email: ronnekle{at}ohsu.edu

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 (V_hold = –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 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.

Key words: nonselective cationic channels; Kir channels; GPR54; phospholipase C; diacylglycerol; single-cell RT-PCR

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Received Dec. 3, 2007; revised March 17, 2008; accepted March 19, 2008.

Correspondence should be addressed to either Dr. Martin J. Kelly or Dr. Oline K. Rønnekleiv, Department of Physiology and Pharmacology, L334, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-2098. Email: kellym{at}ohsu.edu or Email: ronnekle{at}ohsu.edu

This article has been cited by other articles:

				J. Clarkson, X. d'Anglemont de Tassigny, A. S. Moreno, W. H. Colledge, and A. E. Herbison Kisspeptin-GPR54 Signaling Is Essential for Preovulatory Gonadotropin-Releasing Hormone Neuron Activation and the Luteinizing Hormone Surge J. Neurosci., August 27, 2008; 28(35): 8691 - 8697. [Abstract] [Full Text] [PDF]

				I. Dumalska, M. Wu, E. Morozova, R. Liu, A. van den Pol, and M. Alreja Excitatory Effects of the Puberty-Initiating Peptide Kisspeptin and Group I Metabotropic Glutamate Receptor Agonists Differentiate Two Distinct Subpopulations of Gonadotropin-Releasing Hormone Neurons J. Neurosci., August 6, 2008; 28(32): 8003 - 8013. [Abstract] [Full Text] [PDF]

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