In:
Aging Cell, Wiley, Vol. 14, No. 6 ( 2015-12), p. 982-994
Abstract:
K C a 1.1 regulates smooth muscle contractility by modulating membrane potential, and age‐associated changes in K C a 1.1 expression may contribute to the development of motility disorders of the gastrointestinal tract. Sphingolipids ( SL s) are important structural components of cellular membranes whose altered composition may affect K C a 1.1 expression. Thus, in this study, we examined whether altered SL composition due to aging may affect the contractility of gastric smooth muscle ( GSM ). We studied changes in ceramide synthases ( C er S ) and SL levels in the GSM of mice of varying ages and compared them with those in young C er S 2‐null mice. The levels of C 16‐ and C 18‐ceramides, sphinganine, sphingosine, and sphingosine 1‐phosphate were increased, and levels of C 22, C 24:1 and C24 ceramides were decreased in the GSM of both aged wild‐type and young C er S 2‐null mice. The altered SL composition upregulated K C a 1.1 and increased K C a 1.1 currents, while no change was observed in K C a 1.1 channel activity. The upregulation of K C a 1.1 impaired intracellular Ca 2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3‐kinase, protein kinase C ζ , c‐ J un N ‐terminal kinases, and nuclear factor kappa‐ B were found to be involved in K C a 1.1 upregulation. Our findings suggest that age‐associated changes in SL composition or C er S 2 ablation upregulate K C a 1.1 via the phosphoinositide 3‐kinase/protein kinase C ζ /c‐ J un N ‐terminal kinases/nuclear factor kappa‐ B ‐mediated pathway and impair Ca 2+ mobilization, which thereby induces the contractile dysfunction of GSM . C er S 2‐null mice exhibited similar effects to aged wild‐type mice; therefore, C er S 2‐null mouse models may be utilized for investigating the pathogenesis of aging‐associated motility disorders.
Type of Medium:
Online Resource
ISSN:
1474-9718
,
1474-9726
DOI:
10.1111/acel.2015.14.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2099130-7
SSG:
12
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