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Alteration of sphingosine‐1‐phosphate with aging induces contractile dysfunction of colonic smooth muscle cells via Ca 2+ ‐activated K + channel (BK Ca ) upregulation
Author(s) -
Shen Xiaoxue,
Zhang Ling,
Jiang Ling,
Xiong Wenjie,
Tang Yurong,
Lin Lin,
Yu Ting
Publication year - 2021
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.14052
Subject(s) - sphingosine , downregulation and upregulation , sphingosine 1 phosphate , calcium in biology , sphingosine kinase , sphingosine kinase 1 , kinase , chemistry , calcium , extracellular , protein kinase c , microbiology and biotechnology , endocrinology , intracellular , medicine , biology , biochemistry , receptor , gene
Background Age‐associated changes alter calcium‐activated potassium channel (BK Ca ) expression of colon. Sphingolipids (SLs) are important cell membrane structural components; altered composition of SLs may affect BK Ca expression. This study investigated the mechanism by which sphingosine‐1‐phosphate (S1P) contributes to age‐associated contractile dysfunction. Methods Fifty male Sprague Dawley rats of different ages were randomly assigned to five age‐groups, namely 3, 6, 12, 18, and 24 months. BK Ca expression, S1P levels, and phosphorylated myosin light chain (p‐MLC) levels were tested in colonic tissues. In the absence and presence of S1P treatment, BK Ca expression, p‐MLC levels, and intracellular calcium mobilization were tested in vitro. BK Ca small interfering RNA (siRNA) was used to investigate whether p‐MLC expression and calcium mobilization were affected by BK Ca in colonic smooth muscle cells (SMCs). The expressions of phosphorylated protein kinase B, c‐Jun N‐terminal kinases (JNKs), extracellular‐regulated protein kinases, nuclear factor kappa‐B (NF‐κB), and protein kinase C ζ (PKC ζ ) were examined to investigate the correlation between S1P and BK Ca . Key Results Sphingosine‐1‐phosphate levels and sphingosine‐1‐phosphate receptor 2 (S1PR2) and BK Ca expressions were upregulated and p‐MLC expression was downregulated in the colonic tissues, age dependently. In the cultured SMCs, S1P treatment increased BK Ca expression and reduced calcium concentration and p‐MLC was observed. BK Ca siRNA increased calcium concentration, and p‐MLC levels significantly compared with control. We also showed that S1P upregulated BK Ca through PKC ζ , JNK, and NF‐κB pathways. Conclusions and Inferences In conclusion, S1P and S1PR2 participate in age‐associated contractile dysfunction via BK Ca upregulation through PKC ζ , JNK, and NF‐κB pathways.