Kv7 channels as pharmacological targets for central nervous system diseases

Neuronal Kv7 (also known as KCNQ) voltage-gated potassium channels are key regulators of membrane excitability, primarily through their contribution to the M-current, a slowly activating and noninactivating potassium conductance that stabilizes the resting membrane potential and limits repetitive firing. Given the central role of the M-current in regulating critical central nervous system functions, it is not surprising that Kv7 channel dysfunction contributes to the onset and progression of a wide range of neuropsychiatric disorders, and that Kv7 channels are primary targets for pharmacological intervention in all these conditions. In this review, we provide a comprehensive overview of the physiological roles of neuronal Kv7 subunits (Kv7.2-Kv7.5) with particular emphasis on their expression patterns during development and across distinct neuronal populations. We also discuss the complex regulatory mechanisms governing Kv7 channel expression, trafficking, and function, including modulation by intracellular signaling pathways and interacting proteins. Particular attention is devoted to the involvement of Kv7 channel dysfunction in epileptic encephalopathies, pain syndromes, and neuropsychiatric conditions, as well as neurodegenerative disorders such as Alzheimer and Parkinson disease, where altered neuronal excitability is a common pathogenic hallmark. Furthermore, we examine the evolving pharmacological landscape of Kv7 channel modulators, from first-generation openers such as retigabine to next-generation agents, repurposed drugs, natural products, and Kv7 modulators currently in clinical development, highlighting both their therapeutic promise and existing challenges. Collectively, available evidence identifies Kv7 channels as versatile and highly attractive pharmacological targets for the treatment of central nervous system disorders characterized by maladaptive changes in neuronal excitability. SIGNIFICANCE STATEMENT: Kv7 channels are central regulators of neuronal excitability and are increasingly recognized as key therapeutic targets in multiple central nervous system disorders. Advancing our understanding of their pathophysiological role may enable the development of more selective and effective treatments for diseases driven by maladaptive changes in neuronal excitability.