Type 1 transmembrane AMPA-receptor regulatory proteins are auxiliary subunits of Kv7.2 voltage-gated potassium channels

Seizures arise from disruption in mechanisms that control neuronal excitability and the M-current is one such mechanism. This low-threshold potassium current modulates neuronal excitability and suppresses repetitive firing. M-channels assemble as tetramers of Kv7 subunits and mutations in the KCNQ2 gene, encoding Kv7.2, are linked to epilepsy and intellectual disabilities. Despite this common epileptogenic mechanism, understanding M-channel regulation remains limited. We identified type 1 TARPs, well-known Transmembrane AMPA-receptors Regulatory proteins, as new interactors of the Kv7.2 subunit of M-channels, characterized the Kv7.2-TARPs interaction and assessed its functional relevance for neuronal excitability.Through co-immunoprecipitation and proximity-ligation assays, we demonstrated that type 1 TARPs and Kv7.2 interact in neurons, with this interaction increasing upon neuronal activation. Co-expression of TARPs (γ2, γ3 and γ4) with Kv7.2 enhanced the channel’s surface expression and potentiated Kv7.2-mediated currents. Conversely, silencing TARP-γ2 in cortical neurons reduced the M-current, suggesting that endogenous TARP-γ2 is necessary for normal M-channel function. TARP-γ2 depletion also impaired the nano-structure organization of Kv7.2 channels. Notably, an intellectual disability-associated variant of TARP-γ2 failed to potentiate M-currents. In a knock-in mouse harboring this variant the hippocampal M-currents were diminished, as determined by a 50% reduction of the medium after burst-hyperpolarization and a decreased response to retigabine, an M-channel activator. Moreover, these defects led to increased susceptibility to pentylenetetrazol-induced seizures, indicating that disruption of the regulation of M-channels by TARP-γ2 is epileptogenic.Collectively, this work provides groundbreaking evidence of a synaptic protein directly involved in neuronal intrinsic excitability regulation, with important implications for epilepsy.