Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York, USA.
Epilepsia. 2024 Sep;65(9):2537-2552. doi: 10.1111/epi.18066. Epub 2024 Aug 1.
Voltage-gated potassium channels are expressed throughout the human body and are essential for physiological functions. These include delayed rectifiers, A-type channels, outward rectifiers, and inward rectifiers. They impact electrical function in the heart (repolarization) and brain (repolarization and stabilization of the resting membrane potential). KCNQx and KCNHx encode K7.x and K11.x proteins, which form delayed rectifier potassium channels. KCNQx and KCNHx channelopathies are associated with both cardiac and neuronal pathologies. These include electrocardiographic abnormalities, cardiac arrhythmias, sudden cardiac death (SCD), epileptiform discharges, seizures, bipolar disorder, and sudden unexpected death in epilepsy (SUDEP). Due to the ubiquitous expression of KCNQx and KCNHx channels, abnormalities in their function can be particularly harmful, increasing the risk of sudden death. For example, KCNH2 variants have a dual role in both cardiac and neuronal pathologies, whereas KCNQ2 and KCNQ3 variants are associated with severe and refractory epilepsy. Recurrent and uncontrolled seizures lead to secondary abnormalities, which include autonomics, cardiac electrical function, respiratory drive, and neuronal electrical activity. Even with a wide array of anti-seizure therapies available on the market, one-third of the more than 70 million people worldwide with epilepsy have uncontrolled seizures (i.e., intractable/drug-resistant epilepsy), which negatively impact neurodevelopment and quality of life. To capture the current state of the field, this review examines KCNQx and KCNHx expression patterns and electrical function in the brain and heart. In addition, it discusses several KCNQx and KCNHx variants that have been clinically and electrophysiologically characterized. Because these channel variants are associated with multi-system pathologies, such as epileptogenesis, K7 channel modulators provide a potential anti-seizure therapy, particularly for people with intractable epilepsy. Ultimately an increased understanding of the role of K channels throughout the body will fuel the development of innovative, safe, and effective therapies for people at a high risk of sudden death (SCD and SUDEP).
电压门控钾通道在人体全身表达，对生理功能至关重要。这些通道包括延迟整流钾通道、A型钾通道、外向整流钾通道和内向整流钾通道。它们影响心脏（复极化）和大脑（复极化和静息膜电位稳定）的电功能。KCNQx 和 KCNHx 编码 K7.x 和 K11.x 蛋白，形成延迟整流钾通道。KCNQx 和 KCNHx 通道病与心脏和神经元病变都有关。这些包括心电图异常、心律失常、心源性猝死（SCD）、癫痫样放电、癫痫发作、双相情感障碍和癫痫猝死（SUDEP）。由于 KCNQx 和 KCNHx 通道的广泛表达，其功能异常尤其有害，增加了猝死的风险。例如，KCNH2 变体在心脏和神经元病变中都具有双重作用，而 KCNQ2 和 KCNQ3 变体与严重和难治性癫痫有关。反复发作和不受控制的癫痫发作导致继发性异常，包括自主神经系统、心脏电功能、呼吸驱动和神经元电活动。即使市场上有多种抗癫痫药物可用，全世界超过 7000 万癫痫患者中有三分之一的癫痫发作仍无法控制（即难治性/耐药性癫痫），这对神经发育和生活质量产生负面影响。为了了解该领域的现状，本综述检查了 KCNQx 和 KCNHx 在大脑和心脏中的表达模式和电功能。此外，还讨论了几种已在临床和电生理学上进行了特征描述的 KCNQx 和 KCNHx 变体。由于这些通道变体与多系统病变有关，如癫痫发生，K7 通道调节剂提供了一种潜在的抗癫痫治疗方法，特别是对难治性癫痫患者。最终，对全身 K 通道作用的深入了解将为高危猝死（SCD 和 SUDEP）人群开发创新、安全和有效的治疗方法提供动力。
