Figure 1. Schematic diagram illustrating the Kiss1-GnRH connection and signaling pathways responsible for kisspeptin-induced depolarization and burst firing of GnRH neurons.

A. Kisspeptin neurons express the conductances (h-, T- and NaP) and corresponding channels (HCN, Ca_V3 and Na_V) that generate burst firing necessary for maximum release of kisspeptin from the nerve terminal. E2 treatment increases the mRNA expression of Kiss1. In addition, the critical currents (I_h and I_T.) are increased by circulating E2. The respective ion channel transcripts (HCN and Ca_V3, as well as Na_V) are also expressed in Kiss1 neurons (dashed lines). E2 regulation of the mRNA expression of these channels is under investigation (manuscript in preparation). Kiss1 neurons also express GABA_B and κ-opioid receptors, which couple to GIRK channels. B. Whole-cell current-clamp recording of spontaneous rebound burst firing recorded from an AVPV/PeN Kiss1 neuron. Arrows indicate the approximate range where the h-current (I_h, blue) and T-type calcium current (I_T, green) and persistent Na current (I_Na, first red arrow) are active to depolarize the cell to threshold for generating an ensemble of fast Na⁺ spikes (I_Na, second red arrow) and AHP currents (I_AHP, magenta) to repolarize the membrane to a hyperpolarized state to reinitiate the burst firing. The I_Na is composed of an initial I_NaP followed by an I_NaT (transient Na current). C. Kisspeptin binds to the Gq-coupled GPR54 receptor to activate phospholipase Cβ (PLCβ), which catabolizes PIP₂, potentiates TRPC channel activity and inhibits the Kir channel activity. PKC, activated by the PIP₂ hydrolysis product diacylglycerol (DAG), inhibits the activity of a calcium-activated slow afterhyperpolarization (sAHP) current. The non-receptor tyrosine (cSRC) kinase, which is activated by kisspeptin/GRP54 signaling, potentiates the activity of TRPC4 channels. Calcium entering the cell via T-type channels facilitates the activation of TRPC channels.