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  • Diabetes-induced colonic slow transit mediated by the up-regulation of PDGFRα+ cells/SK3 in streptozotocin-induced diabetic mice.

Diabetes-induced colonic slow transit mediated by the up-regulation of PDGFRα+ cells/SK3 in streptozotocin-induced diabetic mice.

Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society (2018-03-10)
N-N Song, H-L Lu, C Lu, L Tong, S-Q Huang, X Huang, J Chen, Y-C Kim, W-X Xu
ABSTRACT

A major complication related to gastrointestinal (GI) symptoms in diabetic patients is chronic constipation. Constipation has serious negative impacts on quality of life; however, without a comprehensive understanding of the disease, currently available treatments cannot provide a cure. Platelet-derived growth factor receptor alpha-positive cells (PDGFRα+ cells), which form the SIP syncytium with interstitial cells of Cajal and smooth muscle cells, play important roles in GI motility. In the present study, the contributions of PDGFRα+ cells to diabetes-induced colonic slow transit were investigated in streptozotocin (STZ)-induced diabetic mice. Western blotting, quantitative PCR, contractile experiments, and intracellular recording were used in the present study. The results demonstrated that the colon length was increased in STZ-treated mice. The colonic transit of artificial fecal pellets in vitro was significantly delayed in STZ-treated mice. The mRNA and protein expression of PDGFRα, small-conductance Ca2+ -activated K channels (SK3), and P2Y1 receptors were increased in the colons of STZ-treated mice. In contractile experiments, the colonic smooth muscles were more sensitive to the SK3 agonist and antagonist (CyPPA and apamin) and the P2Y1 agonist and antagonist (MRS2365 and MRS2500) in STZ-treated mice. Intracellular recordings showed the responses of membrane potentials in colonic smooth muscle cells to CyPPA, apamin, MRS2365, and MRS2500 were more sensitive in STZ-treated mice. The electric field stimulation-induced P2Y1/SK3-dependent fast inhibitory junctional potentials (fIJPs) of colonic smooth muscles were more significantly hyperpolarized in STZ-treated mice. These results suggest that the purinergic neurotransmitters/P2Y1/SK3 signaling pathway is up-regulated in the diabetic colons, thereby mediating diabetes-induced colonic slow transit.

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CyPPA, ≥98% (HPLC), solid