Development of drugs which open or close ATP-sensitive KィイD1+ィエD1channels

at -sensitive K - D1+ K - D1(K - D2ATP - D2) channels are key molecules which link the cell's metabolicstatus to its membrane potential. We have determined that pancreatic β-cell K - 2atp - D2 channelcomprises the inward rectifier Kir6.2 and the sulfonylurea receptor SUR1 subunits，while the cardiac K - D2ATP - D2 channel comprises Kir6.2 and SUR2A，我们的目的在这个研究中是为了develop the drugs which open or close thesechannels specifically.我们的结果是遵循.#我们已经确定了regions which confer thesensitivities of the K - D2ATP D2 channels to the sulfonylurea and the K - D2ATP D2 channel openerdiazoxide,by analyzing a series of chimeras between SUR1 and SUR2.#我们已投资于研究成果G-protein on the reconstituted K - 2atp - D2 channels. We have shown that G-protein α subunitdirectly regulates the K - 2atp - D2 channel activity，and that the gulation is different between β-cell and cardiac K - D2ATP - D2 channels，suggesting that the d…我们已调查过的效果，更多的ifference is determined by distinct SUR subunits.#我们已调查过的效果thiazolidinedione derivatives, which are known to improve insulin resistance，on the reconstituted K - D2ATP - D2 channels. Troglitazone inhibited β-cell and cardiac K - D2ATP - D2channels in a dose dependent manner；it inhibited the former at 30-100 μM and the late at 3 μM. This suggests that troglitazone modulatesthe various cellular functions including insulin secretion and muscle contraction especially underischemic condition.# It has been known that K D2ATP D2 channels are expressed in brain，我们已经研究了electrophysiologicalproperties of the K - D2ATP - D2 channel activity in the acutely dissociated neurons from substantianigra pars reticulate (SNr). The pharmacological properties of The channel are similar to those ofthe β-cell K - 2atp - D2 channel. K - 2atp - D2 channel knockout mice generated by targeting theKir6.2 gene （established in Professor Seino's lab in Chiba University）D2ATP D2 channel activity is absent in SNr, are vulnerable to ischemia，suggesting that K - 2atp - D2 channels play an important role in protection against an ischemicinsult . less

ATP-sensitive KィイD1+ィエD1(KィイD2ATPィエD2) channels are key molecules which link the cell's metabolic status to its membrane potential. We have determined that pancreatic β-cell KィイD2ATPィエD2 channel comprises the inward rectifier Kir6.2 and the sulfonylurea receptor SUR1 subunits, while the cardiac KィイD2ATPィエD2 channel comprises Kir6.2 and SUR2A, an isoform of SUR1. Our purpose in this study is to develop the drugs which open or close these channels specifically. Our results are as follows.# We have determined the regions which confer the sensitivities of the KィイD2ATPィエD2 channels to the sulfonylurea and the KィイD2ATPィエD2 channel opener diazoxide, by analyzing a series of chimeras between SUR1 and SUR2.# We have investigated the effects of G-protein on the reconstituted KィイD2ATPィエD2 channels. We have shown that G-protein α subunit directly regulates the KィイD2ATPィエD2 channel activity, and that the regulation is different between β-cell and cardiac KィイD2ATPィエD2 channels, suggesting that the d … More ifference is determined by distinct SUR subunits.# We have investigated the effects of the thiazolidinedione derivatives, which are known to improve insulin resistance, on the reconstituted KィイD2ATPィエD2 channels. Troglitazone inhibited β-cell and cardiac KィイD2ATPィエD2 channels in a dose dependent manner; it inhibited the former at 30-100 μM and the late at 3 μM. This suggests that troglitazone modulates the various cellular functions including insulin secretion and muscle contraction especially under ischemic condition.# It has been known that KィイD2ATPィエD2 channels are expressed in brain, and are especially abundant in substantial nigra. We have studied the electrophysiological properties of the KィイD2ATPィエD2 channel activity in the acutely dissociated neurons from substantia nigra pars reticulate (SNr). The pharmacological properties of the channel are similar to those of the β-cell KィイD2ATPィエD2 channel. KィイD2ATPィエD2 channel knockout mice generated by targeting the Kir6.2 gene (established in Professor Seino's lab in Chiba University), in which KィイD2ATPィエD2 channel activity is absent in SNr, are vulnerable to ischemia, suggesting that KィイD2ATPィエD2 channels play an important role in protection against an ischemic insult. Less