神经酰胺对神经元和成肌细胞膜钠通道的调控及其机制的研究
摘要
神经鞘磷脂是真核动物细胞膜的主要组成成分之一,也是细胞表面特殊的结构域—脂筏—的主要组成成分。神经酰胺(ceramide)是神经鞘磷脂的代谢产物,它是一种具有多种生物功能的脂质第二信使分子,可以改变细胞膜的脂质环境,也可以通过调节细胞内信号通路影响细胞凋亡或者细胞周期。此外,在多种细胞模型中,神经酰胺类似物都可以直接调控K~+和Ca~(2+)离子通道,但它对细胞膜钠通道的调控报导很少。
我们采用了两种细胞模型,大鼠小脑颗粒神经元(cerebellar granule neuron)和大鼠成肌细胞(Myoblast),运用全细胞电流记录方法研究了体外培养的这两种细胞模型中,神经酰胺的一种类似物,C_6-ceramide,对电压依赖性内向Na~+离子电流(I_(Na))的调控作用以及机制。实验结果显示,小脑颗粒神经元上,Na~+通道蛋白的主要亚型是NaV_(1.2),它定位在细胞膜内陷型脂筏(ceveolae)中。在1-100μM的浓度范围内,C_6-ceramide可逆性的抑制I_(Na),但是抑制程度并不和浓度成正比关系。同时,C_6-ceramide并不影响I_(Na)的稳态激活和稳态失活特性。C_6-ceramide的类似物,C_2-ceramide对I_(Na)幅度也产生类似的抑制效果。然而,非活性的神经酰胺类似物,dihydro-C_6-ceramide,则对I_(Na)没有调节作用。C_6-ceramide对I_(Na)的这些作用都可以被细胞内钙释放激动剂咖啡因(Caffeine)所模拟,而细胞内灌注Ca~(2+)拮抗剂BAPTA则可以消除神经酰胺的作用。如果在大鼠小脑颗粒神经元细胞中灌注软诺丁(Ryanodine)敏感的Ca~(2+)受体拮抗剂钌红(rutheniumred)就可以观察到I_(Na)幅度逐渐增大,并且可以阻断C_6-ceramide对I_(Na)的作用,1,4,5-三磷酸肌醇(IP_3)受体的拮抗剂xestospongin C或者肝素(heparin)则不能影响Na~+电流。如果在大鼠成肌细胞内灌注1,4,5-三磷酸肌醇(IP_3)受体的拮抗剂xestospongin C或者肝素来抑制细胞内质网/肌浆网的Ca~(2+)释放,也可以观察到I_(Na)逐渐增大,同时神经酰胺对I_(Na)的作用被消除,注入软丁受体的拮抗剂则没有这种效果。钙成像实验进一步显示,C_6-ceramide可以明显提高细胞内Ca~(2+)离子浓度。
在两种细胞模型中细胞内灌注G蛋白激动剂GTPγS,会导致I_(Na)幅度的逐渐减小,并且显著改变Na~+电流的激活、失活特性。G蛋白抑制剂GDPβS则可以消除C_6-ceramide对I_(Na)的作用,说明C_6-ceramide对I_(Na)的抑制作用很可能是通过G蛋白和磷脂酶C(phospholipase C)途径,激活细胞内Ca~(2+)释放而实现的。在小脑颗粒神经元中,主要是通过软诺丁受体引起胞内Ca~(2+)通道的开放,而成肌细胞中则主要通过IP_3受体介导的Ca~(2+)释放而实现对I_(Na)的调节。这一现象与细胞膜表面的Ca~(2+)离子通道无关。而神经酰胺引起的颗粒神经元凋亡现象也不是通过对Na~+电流的影响实现的。
我们的实验结果初步揭示了生物活性脂类物质可以通过一系列细胞内信号机制影响Na~+电流,但它们之间还有很多问题需要在后续研究中继续探索。
Sphingolipid is one of the major components of eukaryote membrane,and also a major ingredient of lipid raft.Ceramide is a multi-fuctional second messager as a motabolin of sphingolipid,it can alter the lipid environments of cell membrane. Ceramide can induce cell apoptosis or affect cell cycle through modulating the intracellular signal pathway.Besides,ceramide and its analogs modulate K~+ and Ca~(2+) channels directly in many cell types.While it's modulation on Na~+ channels is seldom reported.
Our research use two cell types,the rat cerebellar granule neuron and myoblast. With the method of whole-cell patch clamp recording,we study the modulation mechanism of C_6-ceramide on voltage-dependent inward Na~+ channels in these two cell types in vitro.NaV_(1.2),which is the most prevalent subtype of Na~+ channels in cerebellar granule cell,locates in membrane lipid raft.We find this modulation is associated with membrane lipid raft.Disruption of lipid raft results in loss of modulation of C_6-ceramide significantly.Our results suggest that C_6-ceramide inhibits I_(Na) of cerebellar granule neuron rapidly and reversibly in a dose-dependent manner between 0.01-1μM,dose-independent manner when the concentration is higher, without altering its steady-state activation and inactivation.C_2-ceramide,an active analog of C_6-ceramide,shows a similar inhibitory effect on I_(Na) of granule neuron, while its inactive analog,dihydro-C_6-ceramide,fails to mimik the effect on I_(Na). Application of caffeine(1 mM) to the bath solution could stimulate release of Ca~(2+) from the endoplasmic reticulum and this caused a rapid and marked reduction of I_(Na), while intracellular infusion of 1,2-bis(2-aminophenoxy) ethane-N,N,N9, N9-tetraacetic acid(BAPTA),a fast Ca~(2+)-chelating agent,vanishes the effect of C_6-ceramide on I_(Na).infusion of ruthenium red,a ryonodine-sensitive Ca~(2+) receptor antagonist,into cerebellar granule cells results in gradual increase of I_(Na) amplitude and abolishes the inhibitory effect of C_6-ceramide on I_(Na).Xestospongin C and heparin, potent IP_3 receptor antagonists,fail to affect I_(Na).Intracellular infusion into rat myoblast with xestospongin C or heparin to block the release of Ca~(2+) from sarcoplasmic reticulum and/or endoplasmic reticulum also results in gradual increase of I_(Na) and abolishment of C_6-ceramide on I_(Na),while rethenium red fails to mimik this effect.Further investigation with Ca~(2+) imaging suggests C_6-ceramide can increase intracellular Ca~(2+) concentration significantly.
Intracellular infusion of GTPγS,a potent agonist of G protein,can reduce I_(Na) amplitude significantly in both cell types,the activation and inactivation curves are significantly shifted.GDPβS,a potent G protein inhibitor,abolished the effects of C_6-ceramide on I_(Na).These results indicated that the inhibitory effects of C_6-ceramide on I_(Na) was a downstream reaction of the activation of G protein and phospholipase C (PLC) pathway and intracellular Ca~(2+) release.Ca~(2+) releases from ryanodine-sensitive receptor in cerebellar granule neurons and IP_3 receptor in myoblasts.Extracellular Ca~(2+) and membrane Ca~(2+) channels are not involved in this progress.And the apoptosis of cerebellar granule cells induced by C_6-ceramide is not associated with Na~+ channels.
Our research suggests the downstream reactions of C_6-ceramide on cerebellar granule cell and myoblast,but how they interact with each other needs further investigation.
我们采用了两种细胞模型,大鼠小脑颗粒神经元(cerebellar granule neuron)和大鼠成肌细胞(Myoblast),运用全细胞电流记录方法研究了体外培养的这两种细胞模型中,神经酰胺的一种类似物,C_6-ceramide,对电压依赖性内向Na~+离子电流(I_(Na))的调控作用以及机制。实验结果显示,小脑颗粒神经元上,Na~+通道蛋白的主要亚型是NaV_(1.2),它定位在细胞膜内陷型脂筏(ceveolae)中。在1-100μM的浓度范围内,C_6-ceramide可逆性的抑制I_(Na),但是抑制程度并不和浓度成正比关系。同时,C_6-ceramide并不影响I_(Na)的稳态激活和稳态失活特性。C_6-ceramide的类似物,C_2-ceramide对I_(Na)幅度也产生类似的抑制效果。然而,非活性的神经酰胺类似物,dihydro-C_6-ceramide,则对I_(Na)没有调节作用。C_6-ceramide对I_(Na)的这些作用都可以被细胞内钙释放激动剂咖啡因(Caffeine)所模拟,而细胞内灌注Ca~(2+)拮抗剂BAPTA则可以消除神经酰胺的作用。如果在大鼠小脑颗粒神经元细胞中灌注软诺丁(Ryanodine)敏感的Ca~(2+)受体拮抗剂钌红(rutheniumred)就可以观察到I_(Na)幅度逐渐增大,并且可以阻断C_6-ceramide对I_(Na)的作用,1,4,5-三磷酸肌醇(IP_3)受体的拮抗剂xestospongin C或者肝素(heparin)则不能影响Na~+电流。如果在大鼠成肌细胞内灌注1,4,5-三磷酸肌醇(IP_3)受体的拮抗剂xestospongin C或者肝素来抑制细胞内质网/肌浆网的Ca~(2+)释放,也可以观察到I_(Na)逐渐增大,同时神经酰胺对I_(Na)的作用被消除,注入软丁受体的拮抗剂则没有这种效果。钙成像实验进一步显示,C_6-ceramide可以明显提高细胞内Ca~(2+)离子浓度。
在两种细胞模型中细胞内灌注G蛋白激动剂GTPγS,会导致I_(Na)幅度的逐渐减小,并且显著改变Na~+电流的激活、失活特性。G蛋白抑制剂GDPβS则可以消除C_6-ceramide对I_(Na)的作用,说明C_6-ceramide对I_(Na)的抑制作用很可能是通过G蛋白和磷脂酶C(phospholipase C)途径,激活细胞内Ca~(2+)释放而实现的。在小脑颗粒神经元中,主要是通过软诺丁受体引起胞内Ca~(2+)通道的开放,而成肌细胞中则主要通过IP_3受体介导的Ca~(2+)释放而实现对I_(Na)的调节。这一现象与细胞膜表面的Ca~(2+)离子通道无关。而神经酰胺引起的颗粒神经元凋亡现象也不是通过对Na~+电流的影响实现的。
我们的实验结果初步揭示了生物活性脂类物质可以通过一系列细胞内信号机制影响Na~+电流,但它们之间还有很多问题需要在后续研究中继续探索。
Sphingolipid is one of the major components of eukaryote membrane,and also a major ingredient of lipid raft.Ceramide is a multi-fuctional second messager as a motabolin of sphingolipid,it can alter the lipid environments of cell membrane. Ceramide can induce cell apoptosis or affect cell cycle through modulating the intracellular signal pathway.Besides,ceramide and its analogs modulate K~+ and Ca~(2+) channels directly in many cell types.While it's modulation on Na~+ channels is seldom reported.
Our research use two cell types,the rat cerebellar granule neuron and myoblast. With the method of whole-cell patch clamp recording,we study the modulation mechanism of C_6-ceramide on voltage-dependent inward Na~+ channels in these two cell types in vitro.NaV_(1.2),which is the most prevalent subtype of Na~+ channels in cerebellar granule cell,locates in membrane lipid raft.We find this modulation is associated with membrane lipid raft.Disruption of lipid raft results in loss of modulation of C_6-ceramide significantly.Our results suggest that C_6-ceramide inhibits I_(Na) of cerebellar granule neuron rapidly and reversibly in a dose-dependent manner between 0.01-1μM,dose-independent manner when the concentration is higher, without altering its steady-state activation and inactivation.C_2-ceramide,an active analog of C_6-ceramide,shows a similar inhibitory effect on I_(Na) of granule neuron, while its inactive analog,dihydro-C_6-ceramide,fails to mimik the effect on I_(Na). Application of caffeine(1 mM) to the bath solution could stimulate release of Ca~(2+) from the endoplasmic reticulum and this caused a rapid and marked reduction of I_(Na), while intracellular infusion of 1,2-bis(2-aminophenoxy) ethane-N,N,N9, N9-tetraacetic acid(BAPTA),a fast Ca~(2+)-chelating agent,vanishes the effect of C_6-ceramide on I_(Na).infusion of ruthenium red,a ryonodine-sensitive Ca~(2+) receptor antagonist,into cerebellar granule cells results in gradual increase of I_(Na) amplitude and abolishes the inhibitory effect of C_6-ceramide on I_(Na).Xestospongin C and heparin, potent IP_3 receptor antagonists,fail to affect I_(Na).Intracellular infusion into rat myoblast with xestospongin C or heparin to block the release of Ca~(2+) from sarcoplasmic reticulum and/or endoplasmic reticulum also results in gradual increase of I_(Na) and abolishment of C_6-ceramide on I_(Na),while rethenium red fails to mimik this effect.Further investigation with Ca~(2+) imaging suggests C_6-ceramide can increase intracellular Ca~(2+) concentration significantly.
Intracellular infusion of GTPγS,a potent agonist of G protein,can reduce I_(Na) amplitude significantly in both cell types,the activation and inactivation curves are significantly shifted.GDPβS,a potent G protein inhibitor,abolished the effects of C_6-ceramide on I_(Na).These results indicated that the inhibitory effects of C_6-ceramide on I_(Na) was a downstream reaction of the activation of G protein and phospholipase C (PLC) pathway and intracellular Ca~(2+) release.Ca~(2+) releases from ryanodine-sensitive receptor in cerebellar granule neurons and IP_3 receptor in myoblasts.Extracellular Ca~(2+) and membrane Ca~(2+) channels are not involved in this progress.And the apoptosis of cerebellar granule cells induced by C_6-ceramide is not associated with Na~+ channels.
Our research suggests the downstream reactions of C_6-ceramide on cerebellar granule cell and myoblast,but how they interact with each other needs further investigation.
引文
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