Type I TARPs regulate Kv7.2 potassium channels andsusceptibility to seizures

The M-current is a low-threshold potassium current that modulates neuronal excitability and suppresses repetitive firing. However, the mechanisms regulating M-channel function remain unclear. We identified type I Transmembrane AMPA receptor Regulatory Proteins (TARPs) as M-channel Kv7.2 subunit interactors in cortical neurons, with their interaction increasing upon neuronal depolarization. Co-expression of TARPs with Kv7.2 increased channel surface expression and Kv7.2-mediated currents, while disrupting TARP-{gamma}2 expression in neurons perturbed dendritic Kv7.2 nano-clusters and decreased M-currents. Knock-in mice with an intellectual disability-associated TARP-{gamma}2 variant showed reduced hippocampal M-currents and increased seizure susceptibility, indicating that disrupting TARP-{gamma}2 regulation of Kv7.2-M-channels is epileptogenic. These findings show that TARP-{gamma}2, a synaptic protein crucial for excitatory transmission, also controls intrinsic excitability via M-channels. This discovery provides a link between synaptic transmission and neuronal excitability, with implications for disease, as the interplay between synaptic and intrinsic plasticity is pivotal to how the brain adapts to varying input signals. HighlightsO_LIType I TARPs bind to Kv7.2-M-channels and enhance Kv7.2-mediated currents. C_LIO_LITARP-{gamma}2 governs the neuronal nano-organization and function of Kv7.2 channels. C_LIO_LIIntellectual disability-associated TARP-{gamma}2 variant impairs M-currents and facilitates seizures. C_LIO_LIType I TARPs can serve as molecular integrators of synaptic and intrinsic excitability. C_LI