Hancock Jane M, Weatherall Kate L, Choisy Stéphanie C, James Andrew F, Hancox Jules C, Marrion Neil V
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.
School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.
Heart Rhythm. 2015 May;12(5):1003-15. doi: 10.1016/j.hrthm.2015.01.027. Epub 2015 Jan 22.
Activation of small conductance calcium-activated potassium (SK) channels is proposed to contribute to repolarization of the action potential in atrial myocytes. This role is controversial, as these cardiac SK channels appear to exhibit an uncharacteristic pharmacology.
The objectives of this study were to resolve whether activation of SK channels contributes to atrial action potential repolarization and to determine the likely subunit composition of the channel.
The effect of 2 SK channel inhibitors was assessed on outward current evoked in voltage clamp and on action potential duration in perforated patch and whole-cell current clamp recording from acutely isolated mouse atrial myocytes. The presence of SK channel subunits was assessed using immunocytochemistry.
A significant component of outward current was reduced by the SK channel blockers apamin and UCL1684. Block by apamin displayed a sensitivity indicating that this current was carried by homomeric SK2 channels. Action potential duration was significantly prolonged by UCL1684, but not by apamin. This effect was accompanied by an increase in beat-to-beat variability and action potential triangulation. This pharmacology was matched by that of expressed heteromeric SK2-SK3 channels in HEK293 cells. Immunocytochemistry showed that atrial myocytes express both SK2 and SK3 channels with an overlapping expression pattern.
Only proposed heteromeric SK2-SK3 channels are physiologically activated to contribute to action potential repolarization, which is indicated by the difference in pharmacology of evoked outward current and prolongation of atrial action potential duration. The effect of blocking this channel on the action potential suggests that SK channel inhibition during cardiac function has the potential to be proarrhythmic.
小电导钙激活钾（SK）通道的激活被认为有助于心房肌细胞动作电位的复极化。这一作用存在争议，因为这些心脏SK通道似乎表现出非典型的药理学特性。
本研究的目的是确定SK通道的激活是否有助于心房动作电位复极化，并确定该通道可能的亚基组成。
评估了2种SK通道抑制剂对急性分离的小鼠心房肌细胞电压钳诱发的外向电流、穿孔膜片钳和全细胞膜片钳记录的动作电位时程的影响。使用免疫细胞化学评估SK通道亚基的存在情况。
SK通道阻滞剂蜂毒明肽和UCL1684可降低外向电流的一个重要成分。蜂毒明肽的阻断表现出一定敏感性，表明该电流由同聚体SK2通道携带。UCL1684可显著延长动作电位时程，但蜂毒明肽无此作用。这种作用伴随着逐搏变异性增加和动作电位三角化。这种药理学特性与HEK293细胞中表达的异聚体SK2 - SK3通道相匹配。免疫细胞化学显示心房肌细胞同时表达SK2和SK3通道，且表达模式重叠。
只有推测的异聚体SK2 - SK3通道在生理上被激活以促进动作电位复极化，这由诱发外向电流的药理学差异和心房动作电位时程延长所表明。阻断该通道对动作电位的影响表明，心脏功能期间抑制SK通道有促心律失常的可能性。
