Increased Activation of the TRESK K⁺ Mediates Vago-Vagal Reflex Malfunction in Diabetic Rats

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• 作者：Gintautas Grabauskas¹ ; Xiaoyin Wu¹ ; Il Song¹ ; Shi-Yi Zhou¹ ; Thomas Lanigan² ; Chung Owyang¹ ; ^{owyang@med.umich.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Vagal Afferent Pathway ; Abnormal GI Functions in Diabetes ; Hyperglycemia
• 刊名：Gastroenterology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：151
• 期：5
• 页码：910-922.e7
• 全文大小：3449 K

文摘

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.