| Project/Area Number |
10470021
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Yamagata University |
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Principal Investigator |
ISHII Kuniaki Yamagata University, School of Medicine, Associate Professor, 医学部, 助教授 (10184459)
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| Co-Investigator(Kenkyū-buntansha) |
HOSOYA Yukio Yamagata School of Health Science, Associate Professor, 助教授 (10250945)
YOMOGIDA Shinichi Yamagata University, School of Medicine, Research assistant, 医学部, 助手 (90250802)
ENDOH Masao Yamagata University, School of Medicine, Professor, 医学部, 教授 (40004668)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥11,600,000 (Direct Cost: ¥11,600,000)
Fiscal Year 1999: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1998: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Keywords | human cardiac delayed rectifier / phosphorylation / tyrosine kinase / protein kinase A / protein kinase C / K^+チャネル / 共発現系 / Herg / PYK2 |
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| Research Abstract |
Human cardiac delayed rectifier potassium channel has 2 components, I_<Kr> and I_<KS>. The poreforming subunit of I_<Kr> channel is encoded by HERG and I_<Ks> channel is composed of 2 molecular entities, KvLQT1 and minK.We have investigated on modulation of HERG and KvLQT1-minK channels using a Xenopus oocyte expression system. Stimulation of coexpressed human endothelin receptor (hETR) by ET-1 did not have obvious influence on HERG currents. However, stimulation of coexpressed hETR markedly inhibited KvLQT1-minK currents. To investigate whether tyrosine kinases are involved in the inhibition of the currents by hETR stimulation, oocytes expressing KvLQT1-minK and hETR were pretreated with tyrosine kinase inhibitors. Treatment with tyrosine kinase inhibitors did not attenuate the inhibitory effect of hETR stimulation, but rather enhanced it. Stimulation of hETR is known to activate Ca^<2+> activated Cl^- channel which is present in Xenopus oocytes. Activation of the Cl^- current was transient but obvious at 5 min after hETR stimulation. Tyrosine kinase inhibitors markedly inhibited the enhancement of the Cl^- currents, which suggested that stimulation of hETR caused activation of tyrosine kinases. It has not been determined yet what pathway is involved in activation of tyrosine kinases following hETR stimulation. KvLQT1-minK, hETR and β_1 adrenergic receptor were coexpressed and the effects of receptor stimulation on KvLQTl-minK currents were investigated. Although exclusive modulation of I_<Ks> current by protein kinase A (PKA) and protein kinase C (PKC) has been reported using chemical reagents, we have not observed the exclusive modulation. Effects of extracellular acidosis, which is known to occur in pathophysiological conditions such as ischemia, on HERG currents were also investigated. Most prominent effect of acidosis was acceleration of deactivation kinetics.
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