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

Chunguang Zhang, Troy A. Roepke, Martin Kelly, Oline Ronnekleiv

Research output: Contribution to journalArticle

161 Citations (Scopus)

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

Kisspeptins
Gonadotropin-Releasing Hormone
Neurons
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
Flufenamic Acid
Inwardly Rectifying Potassium Channel
Transient Receptor Potential Channels
Lanthanum
Barium
Reverse Transcription
Reproduction
Sodium
Pharmacology

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Kisspeptin depolarizes gonadotropin-releasing hormone neurons through activation of TRPC-like cationic channels. / Zhang, Chunguang; Roepke, Troy A.; Kelly, Martin; Ronnekleiv, Oline.

In: Journal of Neuroscience, Vol. 28, No. 17, 23.04.2008, p. 4423-4434.

Research output: Contribution to journalArticle

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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.",
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T1 - Kisspeptin depolarizes gonadotropin-releasing hormone neurons through activation of TRPC-like cationic channels

AU - Zhang, Chunguang

AU - Roepke, Troy A.

AU - Kelly, Martin

AU - Ronnekleiv, Oline

PY - 2008/4/23

Y1 - 2008/4/23

N2 - 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.

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 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.

KW - Diacylglycerol

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KW - Kir channels

KW - Nonselective cationic channels

KW - Phospholipase C

KW - Single-cell RT-PCR

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