title: Increased Activation of the TRESK K+Mediates Vago-Vagal Reflex Malfunction in Diabetic Rats.
abstract: OBJECTIVE
  Patients with diabetes have defects in the vagal afferent pathway that result in abnormal gastrointestinal function. We investigated whether selective increased activation of the 2-pore domain potassium channel TRESK (2-pore-domain weak inward-rectifying potassium channel-related spinal cord potassium channel) contributes to nodose ganglia (NG) malfunction, disrupting gastrointestinal function in diabetic rats.
  
  
  METHODS
  We conducted whole-cell current-clamp and single-unit recordings in NG neurons from diabetes-prone BioBreeding/Worcester rats and streptozotocin-induced diabetic (STZ-D) rats and compared them with control rats. NG neurons in rats or cultured NG neurons were exposed to pharmacologic antagonists and/or transfected with short hairpin or small interfering RNAs that reduced expression of TRESK. We then made electrophysiologic recordings and studied gastrointestinal functions.
  
  
  RESULTS
  We observed reduced input resistance, hyperpolarized membrane potential, and increased current threshold to elicit action potentiation in NG neurons of STZ-D rats compared with controls. NG neuron excitability was similarly altered in diabetes-prone rats. In vivo single-unit NG neuronal discharges in response to 30 and 60 pmol cholecystokinin octapeptide were significantly lower in STZ-D rats compared with controls. Reducing expression of the TRESK K+channel restored NG excitability in vitro and in vivo, as well as cholecystokinin 8-stimulated secretion of pancreatic enzymes and secretin-induced gastrointestinal motility, which are mediated by vago-vagal reflexes. These abnormalities resulted from increased intracellular Ca2+in the NG, activating calcineurin, which, in turn, bound to an nuclear factor of activated T cell-like docking site on the TRESK protein, resulting in neuronal membrane hyperpolarization.
  
  
  CONCLUSIONS
  In 2 rate models of diabetes, we found that activation of the TRESK K+channel reduced NG excitability and disrupted gastrointestinal functions.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan.
authors.forename: Gintautas
authors.initials: G
authors.lastname: Grabauskas
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan.
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan.
authors.forename: Il
authors.initials: I
authors.lastname: Song
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan.
authors.forename: Shi-Yi
authors.initials: SY
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Center for Gene Therapy, Ann Arbor, Michigan.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lanigan
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan. Electronic address: owyang@med.umich.edu.
authors.forename: Chung
authors.initials: C
authors.lastname: Owyang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D005769:Gastrointestinal Motility / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D009620:Nodose Ganglion / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D011913:Rats, Inbred BB; D012018:Reflex
chemical_list: D015415:Biomarkers; C546314:Kcnk18 protein, rat; D015221:Potassium Channels
keywords: Abnormal GI Functions in Diabetes; Hyperglycemia; Vagal Afferent Pathway