Autocrine regulation of calcium influx and gonadotropin-releasing hormone secretion in hypothalamic neurons

Gonadotropin-releasing hormone (GnRH) receptors are expressed in hypothalam ic tissues from adult rats, cultured fetal hypothalamic cells, and immortal ized GnRH-secreting neurons (GT1 cells). Their activation by GnRH agonists leads to an overall increase in the extracellular Ca2+-dependent pulsatile release of GnRH. Electrophysiological studies showed that GT1 cells exhibit spontaneous, extracellular Ca2+-dependent action potentials, and that thei r inward currents include Na+, T-type and L-type Ca2+ components. Several t ypes of potassium channels, including apamin-sensitive Ca2+-controlled pota ssium (SK) channels, are also expressed in GT1 cells. Activation of GnRH re ceptors leads to biphasic changes in intracellular Ca2+ concentration ([Ca2 +](i)), with an early and extracellular Ca2+-independent peak and a sustain ed and extracellular Ca2+-dependent plateau phase. During the peak [Ca2+](i ) response, electrical activity is abolished due to transient hyperpolariza tion that is mediated by SK channels. This is followed by sustained depolar ization and resumption of firing with increased spike frequency and duratio n. The agonist-induced depolarization and increased firing are independent of [Ca2+](i) and are not mediated by inhibition of K+ currents, but by faci litation of a voltage-insensitive and store depletion-activated Ca2+-conduc ting inward current. The dual control of pacemaker activity by SK and store depletion-activated Ca2+ channels facilitates voltage-gated Ca2+ influx at elevated [Ca2+](i) levels, but also protects cells from Ca2+ overload. Thi s process accounts for the autoregulatory action of GnRH on its release fro m hypothalamic neurons.