Gonadotropin-releasing hormone (GnRH) activates the M-current in GnRH neurons: An autoregulatory negative feedback mechanism?

GnRH autoregulates GnRH neurons through an ultrashort feedback loop. One potential mechanism is the regulation of K⁺ channel activity through the GnRH receptor. Whereas GnRH inhibits the activity of the M-current in peripheral neurons, there is no direct evidence that the M-current is involved in the autoregulatory pathway of GnRH or if the M-current is expressed in GnRH neurons. The M-current is a noninactivating, subthreshold K⁺ current that inhibits cell excitability and is ubiquitously expressed in the central nervous system. We found that GnRH neurons expressed the neuronal M-current subunits, KCNQ2, -3, and -5 in addition to GnRH receptor (GnRH R1). Therefore, using whole-cell patch clamp recording and single-cell RT-PCR, we explored the effects of mammalian GnRH peptide on enhanced green fluorescent protein-tagged GnRH neurons acutely dispersed as well as in slice preparations. GnRH (100nM) inhibited GnRH neuronal excitability by hyperpolarizing the membrane. In the presence of CdCl₂, BaCl₂, and tetrodotoxin, GnRH activated an outward current in a dose-dependent manner (EC₅₀ 11 nM) in 30% of GnRH neurons. In voltage clamp, the selective M-channel blocker, XE-991, inhibited a K⁺ current in GnRH neurons. XE-991 also antagonized the outward K⁺ current induced by GnRH. Moreover, the GnRH effects on the M-current were blocked by the GnRH R1 antagonist antide. Therefore, these findings indicate that GnRH activates the M-current in a sub-population of GnRH neurons via GnRH R1. This ultrashort circuit is one potential mechanism by which GnRH could modulate its own neuronal excitability through an autoreceptor.