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

ATP-sensitive K I D1 D 1(K D 2 ATP D 2)channels are key molecules which link the cell‘s metabolic status to its membrane potential.We have determined that pancreaticβ-cell KⅡD2 ATPⅡD2 channel comprises the inward rectifier Kir6.2 and the sulfonylurea receptor SUR1 subunits，while the cardiac KⅡD2 ATPⅡD2 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-I D2 ATP-D2 channels to the sulfonylurea and the K-I D2 ATP-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 I D2 ATP D2 channels.We have shown that G-proteinαsubunit directly regulates the K I D2 ATP基因D2 channel activity，and that the regulation is different betweenβ-cell and cardiac K I D2 ATP基因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 I D2 ATPⅡD2 channels。Troglitazone inhibitedβ-cell and cardiac K I D2 ATPⅡD2 channels in a dose dependent manner；it inhibited the former at 30-100µM and the late at 3µM.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 I D2ATP D2channels are expressed in brain and and muscle expressed in brain and especially ischemic condition.#It has been known that Key D2ATP D2chrain。We have studied the electrophysiological properties of the K I D2 ATP ii channel activity in the acutely dissociated neurons from substantia nigra pars reticulate(SNr)。The pharmacological properties of the channel are similar to those of theβ-cell K I D2 ATPⅡD2 channel.K个D2 ATP D2 channel knockout mice generated by targeting the Kir6.2 gene(established in Professor Seino‘s lab in Chiba University)，in which K I D2 ATP D2 channel activity is absent in SNr，are vulnerable to ischemia，suggesting that K I D2 ATP D2 channels play an important role in protection against an ischemic insult.Less：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