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

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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.