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

ABSTRACT

BACKGROUND & AIMS: 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.