IONIC MECHANISMS RELATED TO SECRETION IN PITUITARY CELLS

膜电事件与膜电活动之间的功能耦合 激素从内分泌细胞的胞吐释放是 内分泌腺分泌的生理学。在.的情况下 脑下垂体激素分泌涉及多个膜离子通道 以及耦合刺激和抑制的分子机制 这些离子通道的分泌性谷氨酸受体现在才 被揭露了。许多分泌性谷氨酸受体属于超家族 七种跨膜跨域受体通过鸟嘌呤核苷酸传递信号 结合蛋白(G蛋白)。在这些受体中，有一些是与 多巴胺(D2型)，催乳素分泌的主要调节剂，以及 生长抑素，控制生长激素释放的抑制。其中 这类受体偶联的效应器是钾 和钙离子通道。近年来，许多要素的信号 将多巴胺受体连接到这些离子通道的信号转导通路 已经被克隆了。尤其是被激活的钾通道 这些受体是两个跨膜结构域的成员。 内向整流K通道的超级家族。我们假设这些G- 蛋白质偶联K通道，或GIRK，是 受体激活和分泌抑制。原则性 本研究的目的是：(1)研究分子 涉及GIRK的信号通路的特异性 G蛋白和GIRK通道，(2)关键测试中心 GIRK通道参与分泌调节，以及(3) 检查修改的机制和作用 脱敏等途径。为此，我们将结合分子 增强和干扰G蛋白和通道的方法 功能与电生理和光学分析的通道和 分别表现为分泌行为。所有的实验都将在 大鼠或小鼠垂体瘤中单个分离的垂体腺细胞 细胞。这项研究将使人们对这些事件有更清晰的了解 脑垂体细胞潜在的调节激素分泌。此外, 垂体和垂体多巴胺受体亚型的共同同一性 脑中G蛋白门控钾通道的相似性 组织，表明这些研究可能提供对 这些神经递质在情感性精神障碍和神经中的作用 营养功能的调节。

The functional coupling between membrane electrical events and exocytotic release of hormones from endocrine cells is a key element in the physiology of secretion in endocrine glands. In the case of pituitary hormone secretion several membrane ion channels are involved and the molecular mechanisms coupling stimulatory and inhibitory secretogogue receptors to these ion channels are only now being revealed. Many secretogogue receptors belong to the superfamily of seven membrane spanning domain receptors signal via guanine nucleotide binding proteins (G-proteins). Among such receptors are those for dopamine (D2 type), the primary regulator of prolactin secretion, and somatostatin which governs inhibition of growth hormone release. Among the effectors to which these classes of receptor couple are potassium and calcium channels. In recent years, many elements of the signal transduction pathways linking dopamine receptors to these ion channels have been cloned. In particular the potassium channels activated by these receptors are members of a two transmembrane spanning domain superfamily of inwardly rectifying K channels. We hypothesize these G- protein coupled K channels, or GIRKs, to be the critical link between receptor activation and the inhibition of secretion. The principle objectives of the present study are to (1) examine the molecular specificity of the signaling pathway which involves GIRK both in terms of G-proteins and GIRK channels, (2) to critically test the central involvment of GIRK channels in the regulation of secretion, and (3) to examine the mechanisms and functional role of modifications to the pathway such as desensitization. To this end we will combine molecular methods to both potentiate and interfere with G-protein and channel function with electrophysiological and optical assays of channel and secretory behavior, respectively. All experiments will be performed in single, isolated pituitary cells of the rat or in mouse pituitary tumor cells. This research will lead to a clearer understanding of the events underlying regulated hormone secretion in pituitary cells. In addition, the common identity of dopamine receptor subtypes in both pituitary and brain as well as similarities in G-protein gated K channels in each tissue, suggest that these studies may provide mechanistic insight into the actions of these neurotransmitters in affective disorders and neural regulation of vegetative functions.