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[摘要]：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. RESEARCH DESIGN AND 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(y)4.2. In diabetic DRG neurons, increased intracellular Ca2+ ([Ca2+](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 [Ca2+](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. Diabetes 60:1743-1751, 2011 |
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