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

<p>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 Na_V1.2 and Na_V1.6 channels lead to distinct contributions to AP initiation and backpropagation.  While Na_V1.6 at the distal AIS promotes AP initiation and forward propagation, Na_V1.2 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 (I_NaP) generation at the AIS to increase neuronal gain and the speed of backpropagation.  Since SUMO does not affect Na_V1.6, these effects were attributed to SUMOylation of Na_V1.2.  Moreover, SUMO effects were absent in a mouse engineered to express Na_V1.2-Lys38Gln channels that lack the site for SUMO linkage.  Thus, SUMOylation of Na_V1.2 exclusively controls I_NaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.</p>