Involvement of tyrosine kinase in regulation of ion channel functions and crosstalk between signal transduction systems
Involvement of tyrosine kinase in regulation of ion channel functions and crosstalk between signal transduction systems
批准号:
10470021
负责人:
ISHII Kuniaki
金额:
$7.42万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (B)
财政年份:
1998
资助国家:
日本
项目状态:
已结题
起止时间:
1998 至 1999
中文摘要
人心脏延迟整流钾通道有2个组分,I_2<Kr>和<KS>I_3。I_<Kr>channel由HERG编码,<Ks>由KvLQT 1和minK两个分子实体组成,我们利用爪蟾卵母细胞表达系统研究了HERG和KvLQT 1-minK通道的调控。ET-1刺激共表达的人内皮素受体(hETR)对HERG电流无明显影响。然而,共表达的hETR的刺激显着抑制KvLQT 1-minK电流。为了研究酪氨酸激酶是否参与hETR刺激对电流的抑制,用酪氨酸激酶抑制剂预处理表达KvLQT 1-minK和hETR的卵母细胞。用酪氨酸激酶抑制剂处理并没有减弱hETR刺激的抑制作用,反而增强了它。已知hETR的刺激可以激活存在于爪蟾卵母细胞中的Ca^2+激活的Cl^-通道。Cl^-电流的激活是短暂的,但在hETR刺激后5分钟明显。酪氨酸激酶抑制剂显著抑制Cl^-电流的增强,这表明hETR的刺激引起酪氨酸激酶的激活。尚未确定hETR刺激后酪氨酸激酶的激活涉及何种途径。共表达KvLQT 1-minK、hETR和β_1肾上腺素能受体,观察受体刺激对KvLQT 1-minK电流的影响。虽然<Ks>蛋白激酶A(PKA)和蛋白激酶C(PKC)对电流的专一性调节已有报道,但我们还没有观察到这种专一性调节。细胞外酸中毒,这是已知发生在病理生理条件下,如缺血,对HERG电流的影响也进行了研究。酸中毒最显著的影响是加速失活动力学。
英文摘要
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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Y. Hashimoto et al.: "Changes in the inactivation of rat Kv1.4 K^+ channels induced by varying the number of inactivation particles."J. Biol. Chem.. vol.275. 9358-9362 (2000)
Y. Hashimoto 等人:“通过改变失活颗粒的数量诱导大鼠 Kv1.4 K^ 通道失活的变化。”J.
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通讯作者:
Kuniaki Ishii: "Current Topics in Membranes.Potassium ion channels"Academic Press. 20 (1999)
Kuniaki Ishii:“膜的当前主题。钾离子通道”学术出版社。
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T.W.Claydon et al.: "Inhibition of the K^+ channel Kv1.4 by acidosis : protonation of an extracellular histidine slows the recovery from N-type inactivation."J.Physiol.. vol.526.2. 253-264 (2000)
T.W.Claydon 等人:“酸中毒对 K + 通道 Kv1.4 的抑制:细胞外组氨酸的质子化减缓了 N 型失活的恢复。”J.Physiol.. vol.526.2。
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O,Clement-Chomienne et al.: "Identification, cloning, and expression of rabbit vascular smooth muscle Kv1.5 and comparison with native delayed rectifier K^+ current."J.Physiol.. vol.515.3. 653-667 (1999)
O,Clement-Chomienne 等人:“兔血管平滑肌 Kv1.5 的鉴定、克隆和表达以及与天然延迟整流 K^ 电流的比较。”J.Physiol.. vol.515.3。
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Ishii,K.: "Differential sensitivity of Kvl.4,Kvl.2,and their tandem channel to acidic pH:involvement of a histidine residue in high sensitivity to acidic pH."J.Phar.Exp.Ther.. 296. 405-411 (2001)
Ishii,K.:“Kvl.4、Kvl.2 及其串联通道对酸性 pH 的不同敏感性:组氨酸残基参与对酸性 pH 的高敏感性。”J.Phar.Exp.Ther.. 296. 405
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共 21 条
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