Analysis of the molecular mechanism underlying the regulation of ATP-sensitive K+ channels by drugs

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 16590191
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Shinshu University
• Principal Investigator: YAMADA Mitsuhiko Shinshu University, School of Medicine, Professor, 医学部, 教授 (10263237)
• Project Period (FY): 2004 – 2006
• Keywords: ATP-sensitive K^+ channels / sulfonylurea receptors / ABC proteins / nucleotide-binding domains / nucleotides / allosteric model / K^+ channel openers / Kir6.2

Research Abstract

An ATP-sensitive K^+ (K_<ATP>) channel is composed of four sulfonylurea receptors (SUR) and four Kir6.2 subunits. SUR is a member of the ABC protein superfamily and bears 17 transmembrane domains (TMD) and two nucleotide-binding domains (NBD1 and NBD2). K^+ channel openers such as nicorandil activate K_<ATP> channels by binding to the 17^<th> TMD of SUR2. SUR2A and SUR2B differ only in the C-terminal 42 amino acids and have the same TMD and NBDs. Nevertheless, SUR2B/Kir6.2 channels show〜100 times higher sensitivity to nicorandil than SUR2A/Kir6.2 channels.
In this study, we found the followings by using the molecular biological technique, the patch clamp method and the model prediction. (A) When KATP channels are activated in the presence of intracellular nucleotides, NBD1 and NBD2 in the same SUR molecule form a dimer. (B) C42 regulates the dimerization of NBDs, and NBDs of SUR2B more easily form the dimer than those of SUR2A. (C) There is an allosteric interaction between the 17^<th> TMD and NBDs. (D) Therefore, SUR2B/Kir6.2 channels show higher sensitivity to nicorandil than SUR2A/Kir6.2 channels.

Research Products

• [Journal Article] PtdIns(3,4,5)P3 and Ca^<2+>/calmodulin competitively bind to the RGS domain of RGS4 and reciprocally regulate its action. (2005)
  • Author(s): Ishii, M., et al.
  • Journal Title: Biochemical Journal 385 Pages: 65-73
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A functional role of the C-terminal 42 amino acids of SUR2A and SUR2B in the physiology and pharmacology of cardiovascular ATP-sensitive K^+ channels. (2005)
  • Author(s): Yamada, M., Kurachi, Y.
  • Journal Title: Journal of Molecular Cellular Cardiology 39 Pages: 1-6
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] PtdIns(3,4,5)P3 and Ca^<2+>/calmodulin competitively bind to the RGS domain of RGS4 and reciprocally regulate its action. (2005)
  • Author(s): Ishii, M., Fujita, S., Yamada, M., Hosaka, Y., Kurachi, Y.
  • Journal Title: Biochem. J. 385 Pages: 65-73
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A functional role of the C-terminal 42 amino acids of SUR2A and SUR2B in the physiology and pharmacology of cardiovascular ATP-sensitive K^+ channels. (2005)
  • Author(s): Yamada, M., Kurachi, Y.
  • Journal Title: J. Mol. Cell. Cardiol 39 Pages: 1-6
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The nucleotide-binding domains of sulfonylurea receptor 2A and 2B play different functional roles in nicorandil-induced activation of ATP-sensitive K^+ channels. (2004)
  • Author(s): Yamada, M., Kurachi, Y.
  • Journal Title: Molecular Pharmacology 65 Pages: 1198-1207
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparison of kinetic properties of quinidine and dofetilide block of HERG channels. (2004)
  • Author(s): Tsujimae, K., et al.
  • Journal Title: European Journal of Pharmacology 493 Pages: 29-40
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutation in nucleotide-binding domains of sulfonylurea receptor 2 evokes Na-ATP-dependent activation of ATP-sensitive K^+ channels : Implication for dimerization of nucleotide-binding domains to induce channel opening. (2004)
  • Author(s): Yamada, M., et al.
  • Journal Title: Molecular Pharmacology 66 Pages: 807-816
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential assembly of inwardly rectifying K^+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes. (2004)
  • Author(s): Hibino H., et al.
  • Journal Title: Journal of Biological Chemistry 279 Pages: 44065-44073
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The nucleotide-binding domains of sulfonylurea receptor 2A and 2B play different functional roles in nicorandil-induced activation of ATP-sensitive K^+ channels. (2004)
  • Author(s): Yamada, M., Kurachi, Y.
  • Journal Title: Mol Pharmacol 65 Pages: 1198-1207
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of kinetic properties of quinidine and dofetilide block of HERG channels. (2004)
  • Author(s): Tsujimae, K., Suzuki, S., Yamada, M., Kurachi, Y.
  • Journal Title: Eur. J. Pharmacol 493 Pages: 29-40
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutation in nucleotide-binding domains of sulfonylurea receptor 2 evokes Na-ATP-dependent activation of ATP-sensitive K^+ channels : Implication for dimerization of nucleotide-binding domains to induce channel opening. (2004)
  • Author(s): Yamada, M., Ishii, M., Hibino, H., Kurachi, Y.
  • Journal Title: Mol Pharmacol 66 Pages: 807-816
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differential assembly of inwardly rectifying K^+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes. (2004)
  • Author(s): Hibino, H., Fujita, A., Iwai, K., Yamada, M., Kurachi, Y.
  • Journal Title: J Biol Chem 279 Pages: 44065-44073
  • Description: 「研究成果報告書概要(欧文)」より