Abstract
The mechanism for the earliest response of central neurons to hypoxia-an increase in voltage-gated sodium current (INa)-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 NaV1.2 channels increases INa. The time-course for SUMOylation of single NaV1.2 channels at the cell surface and changes in INa coincide, and both are prevented by mutation of NaV1.2-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 INa in hypoxic brain damage, the SUMO pathway and NaV1.2 are identified as potential targets for neuroprotective interventions.
Highlights
Acute hypoxia contributes to brain damage arising from such common conditions as stroke, heart attack, and head trauma
When O2 was lowered from ambient levels to 5% by perfusion of cells with hypoxic solutions (Plant et al, 2002), the mean peak in voltage-gated sodium current (INa) increased over 40 s to a new, stable level that was ~70% higher, À294 ± 25 pA/pF (Figure 1a and Table 1), reminiscent of increases in INa in response to acute hypoxia reported by others studying rat neurons from the hypothalamus (Horn and Waldrop, 2000) and hippocampus (Raley-Susman et al, 2001)
We show that SUMOylation of NaV1.2 channels at the plasma membrane underlies the immediate increase in INa in response to acute hypoxia in cultured neurons and Chinese Hamster Ovary (CHO) cells
Summary
Acute hypoxia contributes to brain damage arising from such common conditions as stroke, heart attack, and head trauma. The first effect of hypoxia is to increase INa (Boening et al, 1989; Stys et al, 1992); this precedes a series of events that include depolarization of the plasma membrane, excitotoxic elevation of intracellular calcium, mitochondrial dysfunction, ATP depletion, increased production of reactive oxygen species and, cell death (Leao, 1944; Hansen, 1985; Choi, 1990). SCN2a mutations are associated with epilepsy and febrile seizures (Shi et al, 2012)
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