Among the five KCNQ channels, also known as the K_v7 voltage-gated potassium (K_v) channels, KCNQ2–KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2–KCNQ5 are associated with neurological disorders such as epilepsy, deafness, and neuropathic pain. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 and its complexes with the opener retigabine or the blocker linopirdine at overall resolutions of 2.5, 3.1, and 3.3 Å, respectively. In all structures, a phosphatidylinositol 4,5-bisphosphate (PIP₂) molecule inserts its head group into a cavity within each voltage-sensing domain (VSD), revealing an unobserved binding mode for PIP₂. Retigabine nestles in each fenestration, inducing local shifts. Instead of staying within the central pore, linopirdine resides in a cytosolic cavity underneath the inner gate. Electrophysiological analyses of various mutants corroborated the structural observations. Our studies reveal the molecular basis for the modulatory mechanism of neuronal KCNQ channels and provide a framework for structure-facilitated drug discovery targeting these important channels.

在五个KCNQ通道（也称为K _v 7电压门控钾离子（K _v）通道）中，KCNQ2-KCNQ5控制神经元兴奋性。KCNQ2-KCNQ5的功能障碍与神经系统疾病有关，例如癫痫，耳聋和神经性疼痛。在这里，我们报告了人类KCNQ4的低温电子显微镜（cryo-EM）结构及其与开环瑞替加滨或阻滞剂利诺吡丁的复合物，其整体分辨率分别为2.5、3.1和3.3Å。在所有结构中，磷脂酰肌醇4,5-二磷酸（PIP ₂）分子将其头部插入每个电压感应域（VSD）内的空腔中，从而揭示了PIP ₂的未观察到的结合模式。瑞替加滨在每个开窗处都筑巢，从而引起局部移位。利尼吡丁不是停留在中心孔中，而是位于内门下方的胞质腔中。各种突变体的电生理分析证实了结构观察。我们的研究揭示了神经元KCNQ通道调节机制的分子基础，并为针对这些重要通道的结构促进药物发现提供了框架。