title: SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons.
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 increasesINa. The time-course for SUMOylation of single NaV1.2 channels at the cell surface and changes inINacoincide, 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 ofINain hypoxic brain damage, the SUMO pathway and NaV1.2 are identified as potential targets for neuroprotective interventions.
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, United States.
authors.forename: Leigh D
authors.identifier: 0000-0002-1622-1655
authors.initials: LD
authors.lastname: Plant
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, United States.
authors.forename: Jeremy D
authors.identifier: 0000-0002-2644-5257
authors.initials: JD
authors.lastname: Marks
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, United States.
authors.forename: Steve An
authors.identifier: 0000-0001-5207-5061
authors.initials: SA
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D016466:CHO Cells; D002531:Cerebellum / Q000166:cytology; D003412:Cricetulus; D055724:Electrophysiological Phenomena; D006801:Humans; D000860:Hypoxia; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D058207:Sumoylation
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel
keywords: E. coli; SCN2A; SUMO; human; human biology; hypoxia; ischemia; medicine; neuroscience; rat; stroke