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Investigation of Molecular Diversity of ATP-Sensitive K^+ Channels.

ATP 敏感 K^ 通道的分子多样性研究。

基本信息

批准号：
09670716
负责人：
INANOBE Atsushi
金额：
$ 2.05万
依托单位：
Osaka University Faculty of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

ATP-sensitive K^+ (K_<ATP>) channels, which represent a family of K^+ channels inhibited by intracellular ATP, have been found in a variety of tissues including heart, pancreatic beta-cells, skeletal muscle, smooth muscle, and the central nervous system.These K_<ATP> channels are closely related to diverse cellular functions, such as shortening of action potential duration and cellular loss of K^+ ions that occur during metabolic inhibition in heart, insulin secretion from pancreatic beta-cells, smooth muscle relaxation, regulation of skeletal muscle excitability, and neurotransmitter release.Furthermore, other diverse factors such as NDP, pH, Mg^<2+>, polyamine, PIP_2, G proteins, K^+ channel openers and sulfonylurea also modulate the activity of K_<ATP> channels.K_<ATP> channel is composed of two kinds of membrane proteins Kir6.x and SURx.We characterized K_<ATP> channels reconstituted with various combination of subunits expressed in mammalian cell line with patch clamp techniques.The result runs as follows ; 1) The activity of K_<ATP> channel with Kir6.2 and SUR2A is almost same as that of cardiac K_<ATP> channel.2) Spontaneous openings and unitary conductances of Kir6.1 and Kir6.2 are determined with a part of each N- and C-terminus and extracellular linker domain between the two putative membrane-spanning regions, respectively.3) Splicing isoforms of SUR2A and SUR2B which are divergent at C terminus have different sensitivities to both K^+ channel openers and sulfonylurea.4) Although SUR subunits contain the critical binding sites for K^+ channel openers and intracellular nucleotides, the Kir subunits seem to influence the way in which the entire SUR/Kir functional channel complex reacts to these compounds.

ATP敏感性K^+（K_<ATP>）通道是细胞内ATP抑制的K^+通道家族，广泛存在于心脏、胰腺β细胞、骨骼肌、平滑肌和中枢神经系统等多种组织中<ATP>，与多种细胞功能密切相关，如心脏代谢抑制过程中动作电位时程缩短、细胞内K^+丢失等。K_通道具有调节胰岛β细胞胰岛素分泌、平滑肌松弛、调节骨骼肌兴奋性和神经递质释放等功能，此外，NDP、pH、Mg^<2+>、多胺、PIP_2、G蛋白、K^+通道开放剂和磺酰脲类药物等也对K_通道的活性有调节<ATP><ATP><ATP>作用结果表明：1）<ATP>Kir6.2和SUR 2A的K_通道活性与心脏K_通道活性基本相同。2）Kir6.1和Kir6.2的自发开放和单位电导是通过两个跨膜区之间的胞外连接结构域和N端和C端的一部分来确定的<ATP>，SUR 2A和SUR 2B的C端剪接异构体对K^+通道开放剂和磺酰脲的敏感性不同。尽管SUR亚基包含K^+通道开放剂和细胞内核苷酸的关键结合位点，但Kir亚基似乎影响了整个SUR/Kir功能通道复合物与这些化合物反应的方式。