title: Diabetic visceral hypersensitivity is associated with activation of mitogen-activated kinase in rat dorsal root ganglia.
abstract: OBJECTIVE
  Diabetic patients often experience visceral hypersensitivity and anorectal dysfunction. We hypothesize that the enhanced excitability of colon projecting dorsal root ganglia (DRG) neurons observed in diabetes is caused by a decrease in the amplitude of the transient A-type K(+) (I(A)) currents resulting from increased phosphorylation of mitogen-activated protein kinases (MAPK) and reduced opening of K(v)4.2 channels.
  
  
  METHODS
  We performed patch-clamp recordings of colon projecting DRG neurons from control and streptozotocin-induced diabetic (STZ-D) rats. Western blot analyses and immunocytochemistry studies were used to elucidate the intracellular signaling pathways that modulate the I(A) current. In vivo studies were performed to demonstrate that abnormal MAPK signaling is responsible for the enhanced visceromotor response to colorectal distention in STZ-D rats.
  
  
  RESULTS
  Patch-clamp studies demonstrated that I(A) current was diminished in the colon projecting DRG neurons of STZ-D rats. Western blot analysis of STZ-D DRG neurons revealed increases in phosphorylated MAPK and K(V)4.2. In diabetic DRG neurons, increased intracellular Ca(2+) ([Ca(2+)](i)), protein kinase C (PKC), and MAPK were involved in the regulation of I(A) current through modulation of K(v)4.2. Hypersensitive visceromotor responses to colorectal distention in STZ-D rats were normalized by administration of MAPK inhibitor U0126.
  
  
  CONCLUSIONS
  We demonstrated that reduction of the I(A) current in STZ-D DRG neurons is triggered by impaired [Ca(2+)](i) ion homeostasis, and this in turn activates the PKC-MAPK pathways, resulting in decreased opening of the K(v)4.2 channels. Hence, the PKC-MAPK-K(v)4.2 pathways represent a potential therapeutic target for treating visceral hypersensitivity in diabetes.
authors.affiliation: Gastroenterology Research Unit, Department of Internal Medicine,University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Gintautas
authors.initials: G
authors.lastname: Grabauskas
authors.forename: Andrea
authors.initials: A
authors.lastname: Heldsinger
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Wu
authors.forename: Dabo
authors.initials: D
authors.lastname: Xu
authors.forename: Shiyi
authors.initials: S
authors.lastname: Zhou
authors.forename: Chung
authors.initials: C
authors.lastname: Owyang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003106:Colon / Q000294:innervation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology* / Q000201:enzymology*; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000378:metabolism
chemical_list: D051672:Shal Potassium Channels; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium