SUMOylation of NaV1.2 channels regulates the velocity of backpropagating action potentials in cortical pyramidal neurons

Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential electrophysiological properties and distributions of NaV1.2 and NaV1.6 channels lead to distinct contributions to AP initiation and backpropagation. While NaV1.6 at the distal AIS promotes AP initiation and forward propagation, NaV1.2 at the proximal AIS promotes backpropagation of APs to the soma. Here, we show the Small Ubiquitin-like Modifier (SUMO) pathway modulates persistent sodium current (INaP) generation at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect NaV1.6, these effects were attributed to SUMOylation of NaV1.2. Moreover, SUMO effects were absent in a mouse engineered to express NaV1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of NaV1.2 exclusively controls INaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.Electrical recordings (PClamp 9, Microcal Origin 6) Fast fluorescence imaging (Neuroplex, RedShirt Imaging) Compartmental modeling (Neuron, Yale)Funding provided by: Israel Science FoundationCrossref Funder Registry ID: http://dx.doi.org/10.13039/501100003977Award Number: 1384/19Funding provided by: National Heart, Lung, and Blood InstituteCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000050Award Number: R01HL10549The data set includes experimental data obtained in whole-cell recordings from L5 mouse pyramidal neurons in cortical brain slices. The recordings were done in the current clamp (Figures 1-3, 6) or voltage clamp (Figures 4,5) mode, using hardware and software from Molecular Devices. Figure 7 presents the results of the dual whole cell (soma) and loose patch (axon) recordings obtained using hardware and software from Molecular Devices. In part of the experiments, fast fluorescence imaging of the Na+ indicator, SBFI, was performed along with the electrical recording. Fluorescence data were obtained and analyzed using hardware and software from RedShirtImaging. Compartmental modeling was done using the Neuron 8.1 simulation environment