Kisspeptin and gonadotropin-releasing hormone neuronal excitability: Molecular mechanisms driven by 17β-estradiol

Oline K. Rønnekleiv, Chunguang Zhang, Martha A. Bosch, Martin J. Kelly

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Kisspeptin is a neuropeptide that signals via a Gαq-coupled receptor, GPR54, in gonadotropin-releasing hormone (GnRH) neurons and is essential for pubertal maturation and fertility. Kisspeptin depolarizes and excites GnRH neurons primarily through the activation of canonical transient receptor potential (TRPC) channels and the inhibition of K+ channels. The gonadal steroid 17β-estradiol (E2) upregulates not only kisspeptin (Kiss1) mRNA but also increases the excitability of the rostral forebrain Kiss1 neurons. In addition, a primary postsynaptic action of E2 on GnRH neurons is to upregulate the expression of channel transcripts that orchestrate the downstream signaling of kisspeptin in GnRH neurons. These include not only TRPC4 channels but also low-voltage-activated T-type calcium channels and high-voltage-activated L-, N- and R-type calcium channel transcripts. Moreover, E2 has direct membrane-initiated actions to alter the excitability of GnRH neurons by enhancing ATP-sensitive potassium channel activity, which is critical for maintaining GnRH neurons in a hyperpolarized state for the recruitment of T-type calcium channels that are important for burst firing. Therefore, E2 modulates the excitability of GnRH neurons as well as of Kiss1 neurons by altering the expression and/or function of ion channels; moreover, kisspeptin provides critical excitatory input to GnRH neurons to facilitate burst firing activity and peptide release.

Original languageEnglish (US)
Pages (from-to)184-193
Number of pages10
Issue number3
StatePublished - Nov 10 2015


  • Canonical transient receptor potential channels
  • Gonadotropin-releasing hormone
  • Hyperpolarization-activated, cyclic nucleotide-gated current
  • Kisspeptin
  • Persistent sodium current
  • T-type calcium current

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience


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