Abstract
The mechanism for the earliest response of central neurons to hypoxia-an increase in voltage-gated sodium current (I(Na))-has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of Na(V)1.2 channels increases I(Na). The time-course for SUMOylation of single Na(V)1.2 channels at the cell surface and changes in I(Na) coincide, and both are prevented by mutation of Na(V)1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia-induced linkage of SUMO1 to the channels is complete, shifting the voltage-dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of I(Na) in hypoxic brain damage, the SUMO pathway and Na(V)1.2 are identified as potential targets for neuroprotective interventions.