Bai Chang-Xi, Namekata Iyuki, Kurokawa Junko, Tanaka Hikaru, Shigenobu Koki, Furukawa Tetsushi
Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Circ Res. 2005 Jan 7;96(1):64-72. doi: 10.1161/01.RES.0000151846.19788.E0. Epub 2004 Nov 29.
Sarcolemmal Ca2+ entry is a vital step for contraction of cardiomyocytes, but Ca2+ overload is harmful and may trigger arrhythmias and/or apoptosis. To maintain the amount of Ca2+ entry within an appropriate range, cardiomyocytes have feedback systems that tightly regulate ion channel activities in response to the changes in intracellular Ca2+ concentration ([Ca2+]i), thereby regulating Ca2+ entry. In guinea pig ventricular myocytes, Ca2+ ionophore, A23187, induced suppression of the L-type Ca2+ currents (I(Ca,L)) and enhancement of the slowly activating delayed rectifier K(+) currents (I(Ks)). At a low stimulation rate, I(Ca,L) suppression and I(Ks) enhancement contributed to the A23187-induced APD shortening with a similar magnitude, whereas at a high stimulation rate, I(Ks) enhancement dominantly contributed to APD shortening. I(Ks) enhancement induced by A23187 was attributable to actions of nitric oxide (NO), because they were inhibited by an inhibitor of NO synthase (NOS) and by a NO scavenger. A23187-induced alterations of APD and I(Ks) were strongly suppressed by a NOS3 inhibitor, but barely affected by a NOS1 inhibitor, suggesting that NOS3 was responsible for NO release in this phenomenon. Inhibition of calmodulin (CaM), but not Akt, blocked the enhancement of I(Ks) by A23187. Thus, CaM-dependent NOS3 activation confers the selective Ca2+-sensitivity on I(Ks). Ca2+-induced I(Ks) enhancement and resultant APD shortening potentially act as a physiological regulatory mechanism of Ca2+ recycling, because they were observed at a physiological range of [Ca2+]i in cardiac myocytes and are induced by physiologically relevant Ca2+ loading, such as digitalis application and rise in extracellular Ca2+ concentration.
肌膜Ca2+内流是心肌细胞收缩的关键步骤，但Ca2+超载是有害的，可能引发心律失常和/或细胞凋亡。为了将Ca2+内流的量维持在适当范围内，心肌细胞具有反馈系统，可根据细胞内Ca2+浓度（[Ca2+]i）的变化严格调节离子通道活性，从而调节Ca2+内流。在豚鼠心室肌细胞中，Ca2+离子载体A23187可诱导L型Ca2+电流（I(Ca,L)）受到抑制，缓慢激活延迟整流钾电流（I(Ks)）增强。在低刺激频率下，I(Ca,L)抑制和I(Ks)增强对A23187诱导的动作电位时程（APD）缩短的贡献程度相似，而在高刺激频率下，I(Ks)增强对APD缩短起主要作用。A23187诱导的I(Ks)增强归因于一氧化氮（NO）的作用，因为它们被NO合酶（NOS）抑制剂和NO清除剂所抑制。A23187诱导的APD和I(Ks)改变被NOS3抑制剂强烈抑制，但几乎不受NOS1抑制剂影响，这表明NOS3在此现象中负责NO释放。抑制钙调蛋白（CaM）而非Akt可阻断A23187对I(Ks)的增强作用。因此，CaM依赖的NOS3激活赋予I(Ks)选择性Ca2+敏感性。Ca2+诱导的I(Ks)增强及由此导致的APD缩短可能作为Ca2+再循环的生理调节机制，因为它们在心肌细胞[Ca2+]i的生理范围内被观察到，且由生理相关的Ca2+负荷诱导，如洋地黄应用和细胞外Ca2+浓度升高。
