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Molecular Biology and Genetics of Ion Channels in beta-cells : their roles in diabetes mellitus.

β 细胞离子通道的分子生物学和遗传学：它们在糖尿病中的作用。

基本信息

批准号：
06044036
负责人：
SEINO Susumu
金额：
$ 9.41万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Calcium influx in pancreatic beta-cells is regulated mainly by L-type voltage-dependent calcium channels (VDCCs) and tiggers insulin secretion. The alpha1 subunit (CACN4) and the beta subunit (beta3) of VDCCs, both of which are expressed in pancreatic islets, are major components for the VDCC activity, and so they may play a critical role in the regulation of insulin secretion. We determined the structures of the human CACN4 (CACNL1A2) and the human beta3 (CACNLB3) genes. The CACNLlA2 gene spans more than 155kb and has 49 exons. On the ohter hand, the CACNLB3 gene distributes in -8 kb and comprises 13 exons, most of which are located together within -5 kb. Comparisons of the genomic sequences of CACNL1A2 with the previously reported cDNA sequences indicate that there are a number of polymorphisms in the human CACNL1A2 gene.ATP-sensitive K^+ channls (K_<ATP> channels) in pancreatic beta-cells, are key molecules in the regulation of glucose-induced insulin secretion, by linking the metabolic status to the membrane potential. Furthermore, K_<ATP> channels are the target for sulfonylureas, oral hypoglycemic agents widely used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). We have cloned a novel member of the inwardly rectifying K^+ channels family, designated BIR (Kir6.2). BIR is expressed at high levels in pancreatic islets and glucose-responsive insulin-secreting cell lines. Coexpression with the sulfonylurea receptor, SUR,reconstituted ATP-sensitive K^+ channel properties similar to those found in native pancreatic beta-cells, indicating that pancreatic beta-cell K_<ATP> channels are a complex composed of at least two subunits, BIR and SUR.Gene mapping data showed these two K_<ATP> channel subunit genes to be clustered on chromosome 11 at position 11p15.1.Identification of VDCC and K_<ATP> channel in pancreatic beta-cells should provide a better understanding of their roles in the development of diabetes mellitus.

胰岛β细胞内钙内流主要受L型电压依赖性钙通道(VDCC)和跳跳虎胰岛素分泌的调节。VDCC的α1亚基(CACN4)和β亚基(β3)均表达于胰岛，是VDCC活性的主要成分，可能在胰岛素分泌调节中起关键作用。我们测定了人CACN4(CACNL1A2)和人Beta3(CACNLB3)基因的结构。CACNLlA2基因全长155kb，有49个外显子。CACNLB3基因分布在-8kb内，由13个外显子组成，大部分外显子集中分布在-5kb内。将CACNL1A2的基因组序列与已报道的cDNAs序列进行比较，发现CACNL1A2基因具有一定的多态性。胰岛β细胞中的ATP敏感性K^+通道(K_&lt；ATP&gt；通道)通过将代谢状态与膜电位联系起来，是调节葡萄糖诱导的胰岛素分泌的关键分子。此外，K&lt；ATP&gt；通道是磺脲类药物的靶点，这些口服降糖药被广泛用于治疗非胰岛素依赖型糖尿病(NIDDM)。我们克隆了内向整流性K~+通道家族的一个新成员，命名为BIR(Kir6.2)。BIR在胰岛和对葡萄糖反应的胰岛素分泌细胞系中高水平表达。与磺脲受体SUR共表达的重组K^+通道特性与天然胰岛β细胞相似，提示胰岛β细胞K+通道至少由BIR和SIR两个亚基组成。基因图谱显示这两个K通道亚单位基因聚集在11号染色体11p15.1位。鉴定VDCC和胰岛β细胞中的K+通道有助于更好地了解它们在糖尿病发病中的作用。