Dataset Information

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.

SUBMITTER: Grabauskas G

PROVIDER: S-EPMC5159314 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Grabauskas Gintautas G Wu Xiaoyin X Song Il I Zhou Shi-Yi SY Lanigan Thomas T Owyang Chung C

Gastroenterology 20160727 5

<h4>Background & aims</h4>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.<h4>Methods</h4>We conducted whole-cell current-clamp and si ...[more]

PMID: 27475306

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Project description:RationaleThe signal transduction of remote ischemic conditioning is still largely unknown.ObjectiveCharacterization of neurohumoral signal transfer and vago-splenic axis in remote ischemic preconditioning (RIPC).Methods and resultsAnesthetized pigs were subjected to 60 minutes of coronary occlusion and 180 minutes of reperfusion (placebo+ischemia/reperfusion [PLA+I/R]). RIPC was induced by 4×5/5 minutes of hindlimb I/R 90 minutes before coronary occlusion (RIPC+I/R). Arterial blood samples were taken after placebo or RIPC before I/R. In subgroups of pigs, bilateral cervical vagotomy, splenectomy, or splenic denervation were performed before PLA+I/R or RIPC+I/R, respectively. In pigs with RIPC+I/R, infarct size (percentage of area at risk) was less than in those with PLA+I/R (23±12% versus 45±8%); splenectomy or splenic denervation abrogated (splenectomy+RIPC+I/R: 38±15%; splenic denervation+RIPC+I/R: 43±5%), and vagotomy attenuated (vagotomy+RIPC+I/R: 36±11%) RIPC protection. RIPC increased phosphorylation of STAT3 (signal transducer and activator of transcription 3) in left ventricular biopsies taken at early reperfusion. Splenectomy or splenic denervation, but not vagotomy, abolished this increased phosphorylation. In rats with vagotomy, splenectomy, or splenic denervation, RIPC (3×5/5 minutes of hindlimb occlusion/reperfusion) or placebo was performed, respectively. Hearts were isolated, saline perfused, and subjected to 30/120-minute global I/R. With RIPC, infarct size (percentage of ventricular mass) was less (20±7%) than with placebo (37±6%), and vagotomy, splenectomy, or splenic denervation abrogated RIPC protection (38±12%, 36±9%, and 36±7%), respectively. Rat spleens were isolated, saline perfused, and splenic effluate (SEff) was sampled after infusion with carbachol (SEffcarbachol) or saline (SEffsaline). Pig plasma or SEff was infused into isolated perfused rat hearts subjected to global I/R. Infarct size was less with infusion of RIPC+I/Rplasma+ (24±6%) than with PLA+I/Rplasma (40±8%), vagotomy+PLA+I/Rplasma (39±11%), splenectomy+PLA+I/Rplasma (35±8%), vagotomy+RIPC+I/Rplasma (40±9%), splenectomy+RIPC+I/Rplasma (33±9%), or splenic denervation+RIPC+I/Rplasma (39±8%), respectively. With infusion of SEffcarbachol, infarct size was less than with infusion of SEffsaline (24 [19-27]% versus 35 [32-38]%).ConclusionsActivation of a vago-splenic axis is causally involved in RIPC cardioprotection.

Dataset Information

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

Background & aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background & aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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