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Gastroenterology. 2016 Nov;151(5):910-922.e7. doi: 10.1053/j.gastro.2016.07.029. Epub 2016 Jul 27.

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

Author information

1
Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan.
2
Department of Internal Medicine, Center for Gene Therapy, Ann Arbor, Michigan.
3
Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan. Electronic address: owyang@med.umich.edu.

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.

KEYWORDS:

Abnormal GI Functions in Diabetes; Hyperglycemia; Vagal Afferent Pathway

PMID:
27475306
PMCID:
PMC5159314
DOI:
10.1053/j.gastro.2016.07.029
[Indexed for MEDLINE]
Free PMC Article

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