EXOCYTOSIS AND LATROTOXIN RECEPTOR IN CHROMAFFIN CELLS

描述：这是首次提交的请求续签的建议书 一位富有成效的资深调查员提供的长期资助。它延续了一种 研究胞吐作用的各个方面的一系列研究。 这份意见书的重点是Cirl，一种识别 黑寡妇蜘蛛毒液的活性成分--α-乳杆菌毒素。 已知甲型乳杆菌毒素在脂质中形成非选择性阳离子孔道 但在细胞膜中需要一些辅因子(S)。CIRL是 显然，α-LTX与细胞膜结合的能力至关重要， 而CIRL与孔道孔道形成之间的函数关系 阿尔法-LTX尚不清楚。一个需要解决的关键问题是，阿尔法-LTX 通过简单地将毛孔系在一起形成毛孔，或者毛孔是否 通过激活CIRL而形成的。在这方面，申请人已 研究表明，CIRL类似于7-TM型受体。Cirl有一个可劈开的 胞外α-LTX结合域，以及7-TM结构域，具有中等程度的 与分泌素受体的同源性和同源性。CIRL还可以绑定到 Synaxin。这最后一个特征构成了设计用于 评估CIRL对G蛋白和合成素的影响。这 应用代表了对CIRL的广泛的结构-功能研究。

DESCRIPTION This is the first submission of a proposal requesting renewal of a long-standing grant from a productive senior investigator. It continues a series of studies which have investigated various aspects of exocytosis. The focus of this submission is CIRL, a receptor that recognizes alpha-latrotoxin, an active component of black widow spider venom. Alpha-latrotoxin is known to form non-selective cation pores in lipid bilayers, but in cell membranes requires some cofactor(s). CIRL is apparently critical in the ability of alpha-Ltx to bind to cell membranes, but the functional relationship of CIRL to channel pore formation by alpha-Ltx is not known. A key question to be addressed is whether alpha-Ltx forms pores directly simply by tethering to CIRL, or whether the pores are formed through the activation of CIRL. In that regard, the applicant has shown that CIRL resembles a 7-TM type receptor. CIRL has a cleavable extracellular alpha-Ltx binding domain, and a 7-TM domain that has moderate identity and homology with secretin receptors. CIRL can also bind to syntaxin. This last feature forms the basis for studies designed to evaluate the effects of CIRL on both G proteins, and on syntaxin. This application represents a broad based structure-function study of CIRL.