Open AccessAltering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via K C a 1.1 upregulation
Author(s) -
Choi Shinkyu,
Kim Ji Aee,
Kim Tae Hun,
Li Haiyan,
Shin KyongOh,
Lee YongMoon,
Oh Seikwan,
PewznerJung Yael,
Futerman Anthony H.,
Suh Suk Hyo
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12388
Subject(s) - downregulation and upregulation , biology , sphingolipid , microbiology and biotechnology , composition (language) , smooth muscle , biochemistry , endocrinology , gene , linguistics , philosophy
Summary 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.