小电导K +通道对窦房结起搏的作用：心房特异性Na+ / Ca2+交换体基因敲除小鼠的见解

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Contribution of small conductance K+ channels to sinoatrial node pacemaker activity: insights from atrial-specific Na+ /Ca2+ exchange knockout mice

背景与目的

钾离子通道复极电流对窦房结正常起搏至关重要，但是内向Ca²⁺电流对窦房结复极的影响尚不清楚。我们定义了小鼠窦房结中三种由小电导-Ca²⁺-激活K⁺通道（SK）亚型。SK通道阻滞剂减慢窦房结细胞的复极化及随后的去极化。在心房特异性Na⁺ /Ca²⁺交换体基因敲除小鼠中，窦房结自动起搏诱导细胞内Ca²⁺蓄积产生SK通道间歇性活化，从而导致不规律的短阵起搏。这些发现表明小电导-Ca²⁺-激活K⁺通道可以将细胞内Ca²⁺的变化转化为能够调节起搏的复极电流。SK通道是调节SAN起搏或治疗SAN功能障碍的潜在治疗靶点，特别是在舒张期Ca²⁺异常升高的情况下。小电导K⁺（SK）通道被认为是可能参与心律失常相关的自动去极化和电传导的调节剂。然而，他们的存在和他们对窦房结（SAN）起搏的作用还没有研究。

方  法

我们使用PCR定量（q-PCR），免疫染色和膜片钳电流记录，研究小鼠SAN中的三种SK亚型（SK1，SK2和SK3）。蜜蜂神经毒素（Apamin）可以抑制离体SAN细胞的SK通道并延长动作电位（APs）。Apamin还能减慢舒张期去极化并减少离体SAN细胞和完整窦房结组织的起搏频率。我们研究了SK通道的Ca²⁺敏感性是否作为心房特异性Na⁺ /

Ca²⁺交换体基因敲除小鼠窦房结起搏不规律的解释。这种基因敲除小鼠的离体SAN细胞显示出SK电流较野生型（WT）更高，并且apamin延长Aps。SK抑制剂可以抑制部分不规律的短阵起搏。

结  果

SK通道可以影响小鼠SAN起搏。它们的Ca²⁺依赖性激活将细胞Ca²⁺的变化转化为能够调节规律起搏的复极电流。当Ca²⁺升高时，这Ca²⁺依赖性也会促进异常自律。

结  论

本研究表明在Ca²⁺超载的情况下，可把SK通道作为调节窦房结（SAN）异常起搏以及治疗SAN功能障碍的潜在靶点。

原始文献摘要

Torrente A G, Zhang R, Wang H, et al. Contribution of small conductance K+ channels to sinoatrial node pacemaker activity: insights from atrial‐specific Na+/Ca2+ exchange knockout mice[J]. Journal of Physiology, 2017, 595.

Bacground:

Repolarizing currents through K⁺ channels are essential for proper sinoatrial node (SAN) pacemaking, but the influence of intracellular Ca²⁺ on repolarization in the SAN is uncertain. We identified all three isoforms of Ca²⁺ -activated small conductance K⁺ (SK) channels in the murine SAN. SK channel blockade slows repolarization and subsequent depolarization of SAN cells. In the atrial-specific Na⁺ /Ca²⁺ exchanger (NCX) knockout mouse, cellular Ca²⁺ accumulation during spontaneous SAN pacemaker activity produces intermittent hyperactivation of SK channels, leading to arrhythmic pauses alternating with bursts of pacing. These findings suggest that Ca²⁺ -sensitive SK channels can translate changes in cellular Ca²⁺ into a repolarizing current capable of modulating pacemaking. SK channels are a potential pharmacological target for modulating SAN rate or treating SAN dysfunction, particularly under conditions characterized by abnormal increases in diastolic Ca²⁺ .Small conductance K⁺ (SK) channels have been implicated as modulators of spontaneous depolarization and electrical conduction that may be involved in cardiac arrhythmia. However, neither their presence nor their contribution to sinoatrial node (SAN) pacemaker activity has been investigated.

Methods:

Using quantitative PCR (q-PCR), immunostaining and patch clamp recordings of membrane current and voltage, we identified all three SK isoforms (SK1, SK2 and SK3) in mouse SAN. Inhibition of SK channels with the specific blocker apamin prolonged action potentials (APs) in isolated SAN cells. Apamin also slowed diastolic depolarization and reduced pacemaker rate in isolated SAN cells and intact tissue. We investigated whether the Ca²⁺ -sensitive nature of SK channels could explain arrhythmic SAN pacemaker activity in the atrial-specific Na⁺ /Ca²⁺ exchange (NCX) knockout (KO) mouse, a model of cellular Ca²⁺ overload. SAN cells isolated from the NCX KO exhibited higher SK current than wildtype (WT) and apamin prolonged their APs. SK blockade partially suppressed the arrhythmic burst pacing pattern of intact NCX KO SAN tissue.

Results:

We conclude that SK channels have demonstrable effects on SAN pacemaking in the mouse. Their Ca²⁺ -dependent activation translates changes in cellular Ca²⁺ into a repolarizing current capable of modulating regular pacemaking. This Ca²⁺ dependence also promotes abnormal automaticity when these channels are hyperactivated by elevated Ca²⁺ .

Conclusions:

We propose SK channels as a potential target for modulating SAN rate, and for treating patients affected by SAN dysfunction, particularly in the setting of Ca²⁺ overload.

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