The physiological, intrinsic activity of noradrenergic locus coeruleus (LC) neurons is important for the control of sleep/wakefulness, cognition and autonomous body functions. Dysregulations of the LC-noradrenergic network contribute to the pathogenesis of psychiatric disorders and are key findings in early stages of neurodegenerative diseases. Therefore, identifying ion channels mediating the intrinsic pacemaking mechanism of LC neurons, which is in turn directly coupled to Ca²⁺ homeostasis and cell survival signaling pathways, can help to foster our understanding of the vulnerability of these neurons in neurodegenerative diseases. Small-conductance Ca²⁺-activated K⁺ (SK) channels regulate the intrinsic firing patterns in different central neurons and are essential regulators of the intracellular Ca²⁺ homeostasis. However, the role of SK channels for the intrinsic pacemaking of LC neurons in mice is still unclear. Therefore we performed qPCR expression analysis as well as patch clamp recordings of in vitro brainstem slices, for instance testing SK channel blockers and activators like apamin and NS309, respectively. Although we found a transcriptional expression of SK1, SK2 and SK3 channels, SK2 was the predominantly expressed subunit in mouse LC neurons. Using perforated-patch clamp experiments, we found that SK channels are essential regulators of the intrinsic pacemaking of LC neurons, mediating a large fraction of the afterhyperpolarization (AHP) in these cells. Consistent with a previous observation that a concerted action of L- and T-type Cav channels is essential for the pacemaking of LC neurons, we found that SK channel activation, and the respective AHP amplitude, is primarily coupled to Ca²⁺ influx via these types of Ca²⁺ channels. Our study identified SK2 channels as drug targets for the tuning of the pacemaker frequency in disorders involving a dysregulation of the LC.

去甲肾上腺素能蓝斑（LC）神经元的生理，内在活性对于控制睡眠/清醒，认知和自主身体功能很重要。LC-去甲肾上腺素能网络的失调促成精神疾病的发病机理，并且是神经退行性疾病早期的关键发现。因此，鉴定介导LC神经元内在起搏机制的离子通道可直接与Ca ²⁺稳态和细胞存活信号通路直接偶联，可有助于增进我们对这些神经元在神经退行性疾病中的脆弱性的了解。小电导Ca ²⁺活化K ⁺（SK）通道调节不同中枢神经元内在的放电模式，并且是细胞内Ca ²⁺稳态的重要调节剂。但是，SK通道在小鼠LC神经元内在起搏中的作用仍不清楚。因此，我们进行了qPCR表达分析以及体外膜片钳记录脑干切片，例如分别测试SK通道阻滞剂和激活剂，如apamin和NS309。尽管我们发现了SK1，SK2和SK3通道的转录表达，但SK2是小鼠LC神经元中主要表达的亚基。使用穿孔膜钳实验，我们发现SK通道是LC神经元内在起搏的重要调节剂，在这些细胞中介导了大部分的超极化后（AHP）。与先前的观察结果一致，即L型和T型Cav通道的协同作用对于LC神经元的起搏至关重要，我们发现SK通道激活以及相应的AHP振幅主要通过这些与Ca ^2+内流耦合Ca ^2+的种类渠道。我们的研究确定了在涉及LC失调的疾病中，SK2通道可作为调节起搏器频率的药物靶标。