Microglia are essential to maintain cell homeostasis in the healthy brain and are activated after brain injury. Upon activation, microglia polarize towards different phenotypes. The course of microglia activation is complex and depends on signals in the surrounding milieu. Recently, it has been suggested that microglia respond to ion currents, as a way of regulating their activity and function. Under the hypothesis that HCN and KCNQ/Kv7 channels impact on microglia, we studied primary rat microglia in the presence or absence of specific pharmacological blockade or RNA silencing. Primary microglia expressed the subunits HCN1-4, Kv7.2, Kv7.3, and Kv7.5. The expression of HCN2, as well as Kv7.2 and Kv7.3, varied among different microglia phenotypes. The pharmacological blockade of HCN channels by ZD7288 resulted in cell depolarization with slowly rising intracellular calcium levels, leading to enhanced survival and reduced proliferation rates of resting microglia. Furthermore, ZD7288 treatment, as well as knockdown of HCN2 RNA by small interfering RNA, resulted in an attenuation of later microglia activation—both towards the anti- and pro-inflammatory phenotype. However, HCN channel inhibition enhanced the phagocytic capacity of IL4-stimulated microglia. Blockade of Kv7/KCNQ channel by XE-991 exclusively inhibited the migratory capacity of resting microglia. These observations suggest that the HCN current contributes to various microglia functions and impacts on the course of microglia activation, while the Kv7/KCNQ channels affect microglia migration. Characterizing the role of HCN channels in microglial functioning may offer new therapeutic approaches for targeted modulation of neuroinflammation as a hallmark of various neurological disorders.

中文翻译：

---

超极化激活的环状核苷酸门控（HCN）和电压门控的钾KCNQ / Kv7通道对初级小胶质细胞功能的影响

小胶质细胞对于维持健康大脑中的细胞稳态至关重要，并在脑损伤后被激活。激活后，小胶质细胞会分化为不同的表型。小胶质细胞活化的过程是复杂的，并且取决于周围环境中的信号。最近，已经提出小胶质细胞对离子电流作出反应，作为调节其活性和功能的一种方式。在HCN和KCNQ / Kv7通道影响小胶质细胞的假设下，我们研究了在存在或不存在特定药理封锁或RNA沉默的情况下的原代大鼠小神经胶质细胞。原发性小胶质细胞表达亚单位HCN1-4，Kv7.2，Kv7.3和Kv7.5。HCN2的表达以及Kv7.2和Kv7.3在不同的小胶质细胞表型之间有所不同。ZD7288阻断HCN通道的药理作用导致细胞去极化，细胞内钙水平缓慢升高，从而导致存活率提高和静息小胶质细胞的增殖速率降低。此外，ZD7288处理以及通过小分子干扰RNA敲低HCN2 RNA均会导致后来的小胶质细胞激活减弱（包括抗炎和促炎表型）。但是，HCN通道抑制增强了IL4刺激的小胶质细胞的吞噬能力。XE-991对Kv7 / KCNQ通道的阻断仅抑制了静息小胶质细胞的迁移能力。这些观察结果表明，HCN电流有助于各种小胶质细胞的功能并影响小胶质细胞的激活过程，而Kv7 / KCNQ通道会影响小胶质细胞的迁移。