摘要
大电导钙依赖性钾通道(Large conductance calcium and voltage-dependentpotassium,BK_(Ca)通道)分布广泛,受氧化、磷酸化、胞内钙浓度等因素的调节,在血管、神经内分泌等生理、病理过程中发挥重要的作用。过氧化氢(Hydrogen peroxide,H_2O_2)属于活性氧(ROS)的重要成员,既是细胞损伤的因素,又是胞内的第二信使。PTEN具有负调控PI3K的作用,能调节细胞的大小、生长、凋亡、迁移等,是当前研究的热点之一。本研究以膜片钳技术为基础,结合分子、细胞生物学技术,从H_2O_2对BK_(Ca)通道的作用,PTEN对H_2O_2诱导的BK_(Ca)通道激活的作用和PTEN磷脂酶活性对H_2O_2诱导的BK_(Ca)通道激活的调节等三个方面阐释PTEN、BK_(Ca)通道和H_2O_2之间的相互关系,旨在阐明H_2O_2激活BK_(Ca)通道、舒张血管的分子机制,为进一步探索氧化诱发的心血管疾病机制提供基础。
本文以鼠源BK_(Ca)通道α亚基(Slo)基因(mSlo)在HEK 293细胞表达,运用inside-out和cell-attached两种不同的膜片钳记录模式检测BK_(Ca)通道电流,研究H_2O_2对BK_(Ca)通道的作用。在inside-out模式下,发现以Oμmol Ca~(2+)电极外液灌流时H_2O_2能明显抑制BK_(Ca)通道电流,且DTT对抑制的电流有部分恢复作用。而以10μmolCa~(2+)电极外液灌流时,H_2O_2、DTT对BK_(Ca)通道电流均无明显作用。说明H_2O_2对BK_(Ca)通道的作用主要依靠氧化还原效应影响通道对Ca~(2+)的敏感性。在cell-attached模式下,我们发现H_2O_2能显著、快速增强BK_(Ca)通道活性,表明H_2O_2刺激BK_(Ca)通道能产生两种完全不同的作用。而巯基特异性的氧化剂DTNB在两种模式下均抑制BK_(Ca)通道活性,说明在cell-attached模式下H_2O_2和DTNB对BK_(Ca)通道的作用机制不同。H_2O_2对BK_(Ca)通道的影响受作用方式和H_2O_2浓度的影响。
为了研究PTEN在H_2O_2激活BK_(Ca)通道电流中的作用,我们构建了PTEN-Tdimer2的嵌合基因克隆表达质粒。通过将PTEN_(wt)与mSlo或mSlo和hβ1在HEK 293细胞共转染,在cell-attached模式下记录BK_(Ca)通道电流,发现在PTEN_(wt)过表达的细胞上,不管有无β1的表达,H_2O_2刺激初始10 min都不会明显增加BK_(Ca)通道的活性。此结果不仅说明PTEN能抑制H_2O_2诱导的BK_(Ca)通道激活,而且证实β1亚基的存在并不影响PTEN的作用。进一步以PI3K抑制剂LY294002或Wortmannin孵育细胞,在cell-attached模式下记录电流,发现H_2O_2刺激初始10 min也并不明显增强BK_(Ca)通道活性,说明PI3K参与了H_2O_2诱导的BK_(Ca)通道激活过程。为进一步阐明PI3K/PTEN通路对H_2O_2诱导BK_(Ca)通道激活的生理、病理学意义,我们观测了LY294002对H_2O_2诱导的血管舒张的作用,发现LY294002能明显抑制H_2O_2诱导的血管舒张,但当BK_(Ca)通道阻断剂Iberiotoxin存在时,LY294002的抑制作用消失,说明PI3K是通过BK_(Ca)通道的调节参与H_2O_2诱导的血管环舒张作用。
为了进一步阐明PTEN对H_2O_2激活BK_(Ca)通道的抑制作用机制,将mSlo与磷脂酶活性缺失的PTEN_(C124S)或PTEN_(G129E)在细胞共表达,发现H_2O_2诱导的BK_(Ca)通道激活并没有被抑制,说明PTEN对H_2O_2诱导的BK_(Ca)通道激活的抑制作用主要是通过其磷脂酶活性实现的。针对PTEN蛋白的磷脂酶活性,我们应用Western Blot分析了H_2O_2刺激PTEN_(wt)、PTEN_(C124S)、PTEN_(G129E)过表达细胞产生的p-AKT表达变化,发现H_2O_2刺激初期并不影响PTEN对p-AKT表达的抑制作用,但是在刺激30 min后p-AKT的表达增加,可能与H_2O_2对PTEN的氧化有关。通过激光共聚焦扫描显微镜检测H_2O_2刺激PTEN_(wt)、PTEN_(C124S)、PTEN_(G129E)过表达细胞后胞内钙浓度变化,发现与对照组细胞相比,在PTEN_(wt)过表达细胞中H_2O_2引起胞内钙浓度增加明显降低,时间上显著延长,而在磷脂酶活性缺失的PTEN_(C124S)和PTEN_(G129E)过表达细胞中却没有明显变化。说明H_2O_2诱导的BK_(Ca)通道激活是受PTEN的磷脂酶活性调节,p-AKT、钙浓度的变化可能是作用于BK_(Ca)通道的重要途径。
Large conductance calcium and voltage-dependent potassium(BK_(Ca)) channels are ubiquitously distributed and play a pivotal role in physiological and pathological condition, such as vascular tone,neuronal secretion.In general,the BK_(Ca) channel function is regulated by oxidation,phosphorylation,intracellular calcium concentration and others. H_2O_2 is one of members of Reactive Oxygen Species(ROS) and also plays an important role in physiological and pathological processes.It not only causes oxidative damages to cellular function,but also acts as a second messenger.PTEN negatively controls the activity of PI3K to regulate cellular function,such as cell size,cell growth,apoptosis and migration.In this study,the relationship between H_2O_2,BK_(Ca) channels and PTEN was elucidated by studying the effect of H_2O_2 on BKca channel activity,PTEN and its lipid phosphatase activity on H_2O_2- induced BK_(Ca) channel activation.This study is to prove the molecular mechanism of H_2O_2-induced BK_(Ca) channel activation or vasodilation and provide evidences for discovering the mechanism of oxidation induced vascular diseases.
In this study,BK_(Ca) channel encoded by mouse Slo was heterologously expressed in HEK 293 cells and the typical BKc,channel currents were recorded to study the effects of H_2O_2 on BK_(Ca) channel in inside-out and cell-attached configurations.In inside-out configurations,our results showed that BK_(Ca) channel current was inhibited after exposure to H_2O_2 at 0μmol Ca~(2+) bath solutions,and the inhibition could be reversed partially by DTT.However,the effects of H_2O_2 and DTT on BK_(Ca) channel were abolished at 10μmol Ca~(2+) bath solutions.These data suggested that the effect of H_2O_2 on BK_(Ca) channel is in a voltage and Ca~(2+)-dependent manner and H_2O_2 could decrease the Ca~(2+) sensitivity of channels by thiol oxidation.In cell-attached configuration,we found that NP_o of single BK_(Ca) channels were significantly increased after application of H_2O_2.However,the specific sulfhydryl oxidant DTNB inhibited BK_(Ca) channel NP_o in two different configurations,suggesting that the regulation of BK_(Ca) channels by DTNB and H_2O_2 is different.It also elucidate that the effects of H_2O_2 on BK_(Ca) channels depend on different action modes and H_2O_2 concentrations.
To explore the effect of PTEN on H_2O_2-induced BK_(Ca) channel activation,the PTEN-Tdimer2 plasmids were constructed in our studies.The PTEN-Tdimer2 plasmids and mSlo in the presence or absence of hβ1 were coexpressed in HEK 293 cells and the typical BK_(Ca) channel currents were recorded in cell-attached configuration.Contrary to H_2O_2-induced BK_(Ca) activation,the BK_(Ca) channel currents and conductance in the absence or presence of hβ1 were not changed in PTEN overexpressing cells during the initial 10 min treatment with H_2O_2.It not only suggested that PTEN inhibited H_2O_2-induced BK_(Ca) channel activation,but also verified that the inhibition of PTEN was not affected byβ1. Similarly,the typical BK_(Ca) channel currents were recorded in cell-attached configuration when HEK293 cells expressing mSlo channels were pre-incubated with the PI3K inhibitor LY294002 or Wortmannin for 1 hour.The results showed that the effect of LY294002 or Wortmannin on H_2O_2-induced BK_(Ca) channel activation was same as PTEN,suggesting that PI3K activity is involved in H_2O_2-induced BK_(Ca) channel activation.In order to elucidate the effects of PI3K/PTEN pathway on H_2O_2- induced BK_(Ca) channel activation in physiological and pathological processes,H_2O_2-induced relaxation of isolated rat thoracic aortas was investigated.The results showed that H_2O_2-induced relaxation of aortal rings was decreased by PI3K inhibitor LY294002.However,the effect of LY294002 was abolished in the presence of BK_(Ca) channel inhibitor Iberiotoxin.It suggested that PI3K activity is involved in H_2O_2-induced relaxation of aorta tings via BK_(Ca) channel activation.
To further elucidate the mechanism of PTEN on the inhibiton of H_2O_2-induced BK_(Ca) channel activation,mSlo was coexpressed with catalytically inactive PTEN_(C124S)/ PTENG_(G129E) mutants that lack lipid phosphatase activity.We found that the mutants produced no regulation on the H_2O_2-induced BK_(Ca) channel activation,suggesting that PTEN regulates H_2O_2-induced BK_(Ca) channels activation by acting as a phosphatidylinositol 3-phosphatase.Meanwhile,the p-AKT expression in PTEN_(wt), PTEN_(C124S) and PTEN_(G129E) overexpressing cells after H_2O_2 application was investigated by Western Blot analysis.We found that the p-AKT expression inhibited by PTEN was not changed after H_2O_2 addition for 10 min.However,the inhibition was changed after H_2O_2 addition for 30 min.The results suggested that the change of p-AKT expression may be through oxidation of PTEN by H_2O_2.The cytoplasmic free calcium concentrations ([Ca~(2+)]_i) in PTEN_(wt),PTEN_(C124S) and PTEN_(G129E) overexpressing cells afeer H_2O_2 application were also detected by laser scanning confocal microscopy.We found that the increase of[Ca~(2+)]_i induced by H_2O_2 was also inhibited in PTEN_(wt) overexpressing cells. However,the results were not detected in PTEN_(C124S) and PTEN_(G129E) overexpressing cells. These data suggested that the lipid phosphatase activity of PTEN is involved in H_2O_2-induced BK_(Ca) channel activation,p-AKT and[Ca~(2+)]_i may be important downstream signal molecules for H_2O_2-induced BK_(Ca) channel activation.
引文
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