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Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via K(Ca)1.1 upregulation

Title
Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via K(Ca)1.1 upregulation
Authors
Choi, ShinkyuKim, Ji AeeKim, Tae HunLi, Hai-yanShin, Kyong-OhLee, Yong-MoonOh, SeikwanPewzner-Jung, YaelFuterman, Anthony H.Suh, Suk Hyo
Ewha Authors
서석효최신규
SCOPUS Author ID
서석효scopus; 최신규scopus
Issue Date
2015
Journal Title
AGING CELL
ISSN
1474-9718JCR Link1474-9726JCR Link
Citation
vol. 14, no. 6, pp. 982 - 994
Keywords
Ca2+-activated K+ channelceramide synthasescontractile dysfunctionsmooth musclesphingolipids
Publisher
WILEY-BLACKWELL
Indexed
SCIE; SCOPUS WOS scopus
Abstract
K(Ca)1.1 regulates smooth muscle contractility by modulating membrane potential, and age-associated changes in K(Ca)1.1 expression may contribute to the development of motility disorders of the gastrointestinal tract. Sphingolipids (SLs) are important structural components of cellular membranes whose altered composition may affect K(Ca)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 (CerS) and SL levels in the GSM of mice of varying ages and compared them with those in young CerS2-null mice. The levels of C16- and C18-ceramides, sphinganine, sphingosine, and sphingosine 1-phosphate were increased, and levels of C22, C24:1 and C24 ceramides were decreased in the GSM of both aged wild-type and young CerS2-null mice. The altered SL composition upregulated K(Ca)1.1 and increased K(Ca)1.1 currents, while no change was observed in K(Ca)1.1 channel activity. The upregulation of K(Ca)1.1 impaired intracellular Ca2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3-kinase, protein kinase C zeta, c-Jun N-terminal kinases, and nuclear factor kappa-B were found to be involved in K(Ca)1.1 upregulation. Our findings suggest that age-associated changes in SL composition or CerS2 ablation upregulate K(Ca)1.1 via the phosphoinositide 3-kinase/protein kinase C zeta/c-Jun N-terminal kinases/nuclear factor kappa-B-mediated pathway and impair Ca2+ mobilization, which thereby induces the contractile dysfunction of GSM. CerS2-null mice exhibited similar effects to aged wild-type mice; therefore, CerS2-null mouse models may be utilized for investigating the pathogenesis of aging-associated motility disorders.
DOI
10.1111/acel.12388
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의과대학 > 의학과 > Journal papers
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