Stojilković S S, Iida T, Merelli F, Catt K J
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Mol Pharmacol. 1991 Jun;39(6):762-70.
Endothelin (ET) receptors are present in pituitary cells and stimulate hormone release through the phosphoinositide/Ca2+ signaling system. In pituitary cell suspensions, ET caused [Ca2+]i elevations of much higher amplitudes than those induced by other vasoactive hormones, including angiotensin II, vasopressin, and noradrenalin. The action of ET was coupled to rapid and transient activation of exocytosis in gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. In contrast, angiotensin II did not stimulate luteinizing hormone release, and luteinizing hormone responses to vasopressin and noradrenalin were very small. Single gonadotrophs exhibited three types of [Ca2+]i responses to increasing doses of ET, (a) subthreshold responses, with amplitude modulation; (b) threshold-oscillatory responses, with frequency modulation; and (c) threshold-biphasic responses, as the summation of single Ca2+ spikes. The same [Ca2+]i patterns were also seen in gonadotropin-releasing hormone (GnRH)-stimulated cells. In the presence of [Ca2+]e, the amplitudes of the Ca2+ spikes progressively decreased during continuous stimulation with ET or GnRH, reaching the nonoscillatory plateau level after 200-400 sec of stimulation. In cells stimulated with GnRH, subsequent exposure to ET, GnRH, or ionomycin during the plateau phase did not elicit further increases in [Ca2+]i, whereas cells stimulated with ET responded partially to all three agents. In addition, cells exposed to ET or GnRH for 30 min, followed by a 30-min recovery period, were able to mount a full [Ca2+]i response to GnRH, but not to ET-1. Similarly, both peptides elicited rapid increases in LH release, with comparable potencies, but the response to ET decreased much more rapidly during sustained stimulation and gonadotrophs became refractory to further ET stimulation. This is in part attributable to rapid endocytosis of ET receptors during continuous agonist stimulation. These data indicate that ET exerts potent but transient secretory actions in several pituitary cell types and is a potential regulator of gonadotropin release. The initial receptor-coupling events in both ET- and GnRH-stimulated cells are similar, but the differences observed during continuous or repetitive stimulation indicate that the ET receptor pathway undergoes rapid desensitization that is critical in determining the distinct cellular responses to the two peptides.
内皮素（ET）受体存在于垂体细胞中，并通过磷酸肌醇/Ca2+信号系统刺激激素释放。在垂体细胞悬液中，ET引起的[Ca2+]i升高幅度远高于其他血管活性激素，包括血管紧张素II、血管加压素和去甲肾上腺素所诱导的升高幅度。ET的作用与促性腺激素细胞、促甲状腺激素细胞、生长激素细胞和催乳激素细胞中胞吐作用的快速和短暂激活相关。相比之下，血管紧张素II不刺激促黄体生成素释放，且促黄体生成素对血管加压素和去甲肾上腺素的反应非常小。单个促性腺激素细胞对递增剂量的ET表现出三种类型的[Ca2+]i反应：（a）阈下反应，伴有幅度调制；（b）阈振荡反应，伴有频率调制；（c）阈双相反应，为单个Ca2+峰的总和。在促性腺激素释放激素（GnRH）刺激的细胞中也观察到相同的[Ca2+]i模式。在存在[Ca2+]e的情况下，在用ET或GnRH持续刺激期间，Ca2+峰的幅度逐渐降低，在刺激200 - 400秒后达到非振荡平台水平。在用GnRH刺激的细胞中，在平台期随后暴露于ET、GnRH或离子霉素不会引起[Ca2+]i的进一步增加，而用ET刺激的细胞对所有三种试剂都有部分反应。此外，暴露于ET或GnRH 30分钟，随后有30分钟恢复期的细胞，能够对GnRH产生完整的[Ca2+]i反应，但对ET - 1则不能。同样，两种肽都能快速增加促黄体生成素释放，效力相当，但在持续刺激期间对ET的反应下降得更快，促性腺激素细胞对进一步的ET刺激变得不敏感。这部分归因于持续激动剂刺激期间ET受体的快速内吞作用。这些数据表明，ET在几种垂体细胞类型中发挥强大但短暂的分泌作用，并且是促性腺激素释放的潜在调节因子。ET和GnRH刺激的细胞中最初的受体偶联事件相似，但在持续或重复刺激期间观察到的差异表明，ET受体途径经历快速脱敏，这对于确定细胞对这两种肽的不同反应至关重要。
