Autocrine regulation of calcium influx and gonadotropin-releasing hormone secretion in hypothalamic neurons.
Gonadotropin-releasing hormone (GnRH) receptors are expressed in hypothalamic tissues from adult rats, cultured fetal hypothalamic cells, and immortalized 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 their inward currents include Na+, T-type and L-type Ca2+ components. Several types of potassium channels, including apamin-sensitive Ca2+-controlled potassium (SK) channels, are also expressed in GT1 cells. Activation of GnRH receptors leads to biphasic changes in intracellular Ca2+ concentration ([Ca2+]i), with an early and extracellular Ca2+-independent peak and a sustained and extracellular Ca2+-dependent plateau phase. During the peak [Ca2+]i response, electrical activity is abolished due to transient hyperpolarization that is mediated by SK channels. This is followed by sustained depolarization and resumption of firing with increased spike frequency and duration. The agonist-induced depolarization and increased firing are independent of [Ca2+]i and are not mediated by inhibition of K+ currents, but by facilitation of a voltage-insensitive and store depletion-activated Ca2+-conducting 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. This process accounts for the autoregulatory action of GnRH on its release from hypothalamic neurons.
Van Goor
F
F
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4510, USA. fredrick@box-f.nih.gov
Krsmanovic
L Z
LZ
Catt
K J
KJ
Stojilkovic
S S
SS
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004594:Electrophysiology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D008954:Models, Biological; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats
D015220:Calcium Channels; D015221:Potassium Channels; D007987:Gonadotropin-Releasing Hormone; D011188:Potassium; D002118:Calcium