KV3.1 channel modulation: a systematic review of pharmacological intervention strategies

Abstract

Introduction Voltage-gated potassium channels of the KV3 subfamily, particularly KV3.1 (encoded by KCNC1), are essential regulators of fast-spiking inhibitory interneuron activity and high-frequency neuronal firing, enabling precise control of neuronal excitability and network synchrony. Growing evidence links KV3.1 dysfunction to epilepsy, schizophrenia, tinnitus, fragile X syndrome, amyotrophic lateral sclerosis, and KCNC1 related developmental and epileptic encephalopathies, positioning this channel as a promising therapeutic target. Methods This systematic review, conducted in accordance with PRISMA guidelines, evaluates original studies published between 2016 and January 2026 that investigated pharmacological modulation of KV3.1 using in vitro, in vivo, structural, and translational approaches. Results A total of thirty-two studies met the predefined PICOS criteria. The literature reveals two pharmacological strategies: positive allosteric modulation aimed at enhancing fast-spiking inhibitory interneuron function and restoring excitation inhibition balance, and state-dependent channel inhibition, particularly relevant for pathogenic gain of function KCNC1 variants. Discussion While early positive allosteric modulators demonstrated proof of mechanism with limited clinical success, second-generation compounds exhibit improved translational potential, including evidence that they modulate functional brain networks in humans. In parallel, clinically approved antidepressants have been identified as open-channel blockers of KV3.1, enabling mutation-specific therapeutic repurposing. Conclusions Collectively, these findings highlight KV3.1 modulation as a context-dependent and increasingly precise pharmacological strategy for neurological and neurodevelopmental disorders.