title: Downregulation of the sodium channel Nav1.6 by potential transcriptomic deregulation may explain sensory deficits in critical illness neuropathy.
abstract: OBJECTIVE
  Sepsis patients and other patients in the critical care settings are at very high risk of mortality due to the primary illness. However, a fraction of patients, even after showing initial clinical improvement, deteriorates relentlessly at later stages. Increasingly, it is being identified that this is mostly due to dysfunction of the neurological system.
  
  
  METHODS
  We obtained peripheral nerve biopsies from the sural nerve from ICU patients. Nav1.6 expression was significantly diminished. The expression of cellular membrane anchoring protein for Nav1.6, ankyrin, remained unaffected, suggesting that genomic repression may be responsible for the diminished expression of the sodium channels. We examined the expression of two regulatory transcription factors: (a) a positive regulator YY1 that binds to the promoter region of sodium channels and (b) an upstream negative neuronal regulator REST.
  
  
  RESULTS
  REST expression was significantly elevated, while YY1 expression was diminished. Finally, we also observed that the cholinergic synthetic enzyme acyltransferase was also significantly diminished in sensory nerve lysates. Finally, circulating antibodies was detected in the peripheral blood against all the major sodium channels Nav1.6, 1.8 and 1.9, which contribute to the development and propagation of action potentials.
  
  
  CONCLUSIONS
  This may potentially explain why its dysfunction affects neurological functions across all systems of the body during critical illness. The underlying mechanism of why the expression of the REST transcriptional factor is affected in critical illnesses remains our future goals of investigation.
authors.affiliation: Department of Intensive Care Unit, The First Hospital of Jilin University, Jilin 130021, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Intensive Care Unit, The First Hospital of Jilin University, Jilin 130021, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Intensive Care Unit, The First Hospital of Jilin University, Jilin 130021, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Intensive Care Unit, The First Hospital of Jilin University, Jilin 130021, China. Electronic address: shijingwang_ch@tom.com.
authors.forename: Shiji
authors.initials: S
authors.lastname: Wang
mesh_terms: D000200:Action Potentials / Q000502:physiology; D016638:Critical Illness; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D011115:Polyneuropathies / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis*; D013497:Sural Nerve / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000502:physiology*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C100681:SCN8A protein, human
keywords: Channelopathy; Critical illness polyneuropathy; Sensory deficit; Sodium channel