Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.
Dev Neurosci. 2021;43(3-4):191-200. doi: 10.1159/000515495. Epub 2021 Apr 1.
KCNQ2 and KCNQ3 pathogenic channel variants have been associated with a spectrum of developmentally regulated diseases that vary in age of onset, severity, and whether it is transient (i.e., benign familial neonatal seizures) or long-lasting (i.e., developmental and epileptic encephalopathy). KCNQ2 and KCNQ3 channels have also emerged as a target for novel antiepileptic drugs as their activation could reduce epileptic activity. Consequently, a great effort has taken place over the last 2 decades to understand the mechanisms that control the assembly, gating, and modulation of KCNQ2 and KCNQ3 channels. The current view that KCNQ2 and KCNQ3 channels assemble as heteromeric channels (KCNQ2/3) forms the basis of our understanding of KCNQ2 and KCNQ3 channelopathies and drug design. Here, we review the evidence that supports the formation of KCNQ2/3 heteromers in neurons. We also highlight functional and transcriptomic studies that suggest channel composition might not be necessarily fixed in the nervous system, but rather is dynamic and flexible, allowing some neurons to express KCNQ2 and KCNQ3 homomers. We propose that to fully understand KCNQ2 and KCNQ3 channelopathies, we need to adopt a more flexible view of KCNQ2 and KCNQ3 channel stoichiometry, which might differ across development, brain regions, cell types, and disease states.
KCNQ2 和 KCNQ3 致病通道变体与一系列发育调节疾病相关，这些疾病在发病年龄、严重程度以及是否为短暂性（即良性家族性新生儿癫痫）或持久性（即发育性和癫痫性脑病）方面存在差异。KCNQ2 和 KCNQ3 通道也已成为新型抗癫痫药物的靶点，因为它们的激活可以减少癫痫活动。因此，在过去的 20 年中，人们付出了巨大的努力来理解控制 KCNQ2 和 KCNQ3 通道组装、门控和调节的机制。目前的观点认为，KCNQ2 和 KCNQ3 通道作为异源二聚体通道（KCNQ2/3）组装，这是我们理解 KCNQ2 和 KCNQ3 通道病和药物设计的基础。在这里，我们回顾了支持神经元中 KCNQ2/3 异源二聚体形成的证据。我们还强调了功能和转录组学研究，这些研究表明通道组成在神经系统中不一定是固定的，而是动态和灵活的，允许一些神经元表达 KCNQ2 和 KCNQ3 同源二聚体。我们提出，为了充分理解 KCNQ2 和 KCNQ3 通道病，我们需要对 KCNQ2 和 KCNQ3 通道的计量比采取更灵活的观点，这可能因发育、脑区、细胞类型和疾病状态而异。
