Van Goor F, Krsmanovic L Z, Catt K J, Stojilkovic S S
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4510, USA.
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4101-6. doi: 10.1073/pnas.96.7.4101.
Elevation of cytosolic free Ca2+ concentration ([Ca2+]i) in excitable cells often acts as a negative feedback signal on firing of action potentials and the associated voltage-gated Ca2+ influx. Increased [Ca2+]i stimulates Ca2+-sensitive K+ channels (IK-Ca), and this, in turn, hyperpolarizes the cell and inhibits Ca2+ influx. However, in some cells expressing IK-Ca the elevation in [Ca2+]i by depletion of intracellular stores facilitates voltage-gated Ca2+ influx. This phenomenon was studied in hypothalamic GT1 neuronal cells during store depletion caused by activation of gonadotropin-releasing hormone (GnRH) receptors and inhibition of endoplasmic reticulum (Ca2+)ATPase with thapsigargin. GnRH induced a rapid spike increase in [Ca2+]i accompanied by transient hyperpolarization, followed by a sustained [Ca2+]i plateau during which the depolarized cells fired with higher frequency. The transient hyperpolarization was caused by the initial spike in [Ca2+]i and was mediated by apamin-sensitive IK-Ca channels, which also were operative during the subsequent depolarization phase. Agonist-induced depolarization and increased firing were independent of [Ca2+]i and were not mediated by inhibition of K+ current, but by facilitation of a voltage-insensitive, Ca2+-conducting inward current. Store depletion by thapsigargin also activated this inward depolarizing current and increased the firing frequency. Thus, the pattern of firing in GT1 neurons is regulated coordinately by apamin-sensitive SK current and store depletion-activated Ca2+ current. This dual control of pacemaker activity facilitates voltage-gated Ca2+ influx at elevated [Ca2+]i levels, but also protects cells from Ca2+ overload. This process may also provide a general mechanism for the integration of voltage-gated Ca2+ influx into receptor-controlled Ca2+ mobilization.
可兴奋细胞中胞质游离钙离子浓度（[Ca2+]i）的升高通常作为对动作电位发放及相关电压门控性Ca2+内流的负反馈信号。[Ca2+]i升高会刺激Ca2+敏感的K+通道（IK-Ca），进而使细胞超极化并抑制Ca2+内流。然而，在一些表达IK-Ca的细胞中，细胞内钙库耗竭引起的[Ca2+]i升高却会促进电压门控性Ca2+内流。在促性腺激素释放激素（GnRH）受体激活和用毒胡萝卜素抑制内质网（Ca2+）ATP酶导致钙库耗竭期间，对下丘脑GT1神经元细胞中的这一现象进行了研究。GnRH诱导[Ca2+]i迅速出现尖峰增加并伴有短暂超极化，随后是[Ca2+]i的持续平台期，在此期间去极化细胞以更高频率发放动作电位。短暂超极化是由[Ca2+]i的初始尖峰引起的，并由蜂毒明肽敏感的IK-Ca通道介导，这些通道在随后的去极化阶段也发挥作用。激动剂诱导的去极化和发放增加与[Ca2+]i无关，且不是由K+电流抑制介导的，而是由一种电压不敏感的、Ca2+传导的内向电流的增强介导的。毒胡萝卜素引起的钙库耗竭也激活了这种内向去极化电流并增加了发放频率。因此，GT1神经元的发放模式由蜂毒明肽敏感的SK电流和钙库耗竭激活的Ca2+电流协同调节。这种对起搏器活动的双重控制在[Ca2+]i水平升高时促进电压门控性Ca2+内流，但也保护细胞免受Ca2+过载。这一过程还可能为将电压门控性Ca2+内流整合到受体控制的Ca2+动员中提供一种普遍机制。
