Lachowicz A, Van Goor F, Katzur A C, Bonhomme G, Stojilkovic S S
Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 1997 Nov 7;272(45):28308-14. doi: 10.1074/jbc.272.45.28308.
In cells expressing Ca2+-mobilizing receptors, InsP3-induced Ca2+ release from intracellular stores is commonly associated with extracellular Ca2+ influx. Operation of these two Ca2+ signaling pathways mediates thyrotropin-releasing hormone (TRH) and angiotensin II (AII)-induced prolactin secretion from rat pituitary lactotrophs. After an initial hyperpolarization induced by Ca2+ mobilization from the endoplasmic reticulum (ER), these agonists generated an increase in the steady-state firing of action potentials, further facilitating extracellular Ca2+ influx and prolactin release. Like TRH and AII, endothelin-1 (ET-1) also induced a rapid release of Ca2+ from the ER and a concomitant spike prolactin secretion during the first 3-5 min of stimulation. However, unlike TRH and AII actions, Ca2+ mobilization was not coupled to Ca2+ influx during sustained ET-1 stimulation, as ET-1 induced a long-lasting abolition of action potential firing. This lead to a depletion of the ER Ca2+ pool, a prolonged decrease in [Ca2+]i, and sustained inhibition of prolactin release. ET-1-induced inhibition and TRH/AII-induced stimulation of Ca2+ influx and hormone secretion were reduced in the presence of the L-type Ca2+ channel blocker, nifedipine. Basal [Ca2+]i and prolactin release were also reduced in the presence of nifedipine. Furthermore, TRH-induced Ca2+ influx and secretion were abolished by ET-1, as TRH was unable to reactivate Ca2+ influx and prolactin release in ET-1-stimulated cells. Depolarization of the cells during sustained inhibitory action of ET-1, however, increased [Ca2+]i and prolactin release. These results indicate that L-type Ca2+ channel represents a common Ca2+ influx pathway that controls basal [Ca2+]i and secretion and is regulated by TRH/AII and ET-1 in an opposite manner. Thus, the receptor-mediated uncoupling of Ca2+ entry from Ca2+ mobilization provides an effective control mechanism in terminating the stimulatory action of ET-1. Moreover, it makes electrically active lactotrophs quiescent and unresponsive to other calcium-mobilizing agonists.
在表达可动员钙离子的受体的细胞中，肌醇三磷酸（InsP3）诱导的细胞内钙库释放钙离子通常与细胞外钙离子内流相关。这两条钙离子信号通路的运作介导了促甲状腺激素释放激素（TRH）和血管紧张素II（AII）诱导的大鼠垂体催乳素细胞分泌催乳素。在内质网（ER）释放钙离子引发初始超极化后，这些激动剂使动作电位的稳态发放频率增加，进一步促进细胞外钙离子内流和催乳素释放。与TRH和AII一样，内皮素-1（ET-1）在刺激的最初3 - 5分钟内也诱导内质网快速释放钙离子，并伴随催乳素分泌峰值。然而，与TRH和AII的作用不同，在持续的ET-1刺激过程中，钙离子动员与钙离子内流不偶联，因为ET-1诱导动作电位发放的长期消失。这导致内质网钙库耗竭，细胞内钙离子浓度（[Ca2+]i）持续下降，以及催乳素释放的持续抑制。在L型钙离子通道阻滞剂硝苯地平存在的情况下，ET-1诱导的钙离子内流抑制以及TRH/AII诱导的钙离子内流刺激和激素分泌均减弱。在硝苯地平存在的情况下，基础[Ca2+]i和催乳素释放也减少。此外，ET-1消除了TRH诱导的钙离子内流和分泌，因为在ET-1刺激的细胞中，TRH无法重新激活钙离子内流和催乳素释放。然而，在ET-1持续抑制作用期间使细胞去极化，会增加[Ca2+]i和催乳素释放。这些结果表明，L型钙离子通道代表了一条共同的钙离子内流途径，它控制基础[Ca2+]i和分泌，并受到TRH/AII和ET-1以相反方式的调节。因此，受体介导的钙离子内流与钙离子动员的解偶联为终止ET-1的刺激作用提供了一种有效的控制机制。此外，它使电活动的催乳素细胞静止，并对其他可动员钙离子的激动剂无反应。
