TY - JOUR
T1 - Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via KCa1.1 upregulation
AU - Choi, Shinkyu
AU - Kim, Ji Aee
AU - Kim, Tae Hun
AU - Li, Hai-yan
AU - Shin, Kyong-Oh
AU - Lee, Yong-Moon
AU - Oh, Seikwan
AU - Pewzner-Jung, Yael
AU - Futerman, Anthony H.
AU - Suh, Suk Hyo
N1 - Basic Science Research Program through the Nation Research Foundation of Korea - Ministry of Education, Science and Technology [R01-2010-000-10466-0, NRF-2013R1A1A2010851, NRF-2013R1A1A2064543]; National Research Foundation of Korea - Korean Government [NRF-2010-220-E00001]; Israel Science Foundation [0888/11] This research was supported by Basic Science Research Program through the Nation Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R01-2010-000-10466-0, NRF-2013R1A1A2010851, NRF-2013R1A1A2064543), by the National Research Foundation of Korea Grant funded by the Korean Government (NRF-2010-220-E00001), and by the Israel Science Foundation (0888/11). A.H. Futerman is The Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute. of Science.
PY - 2015/12
Y1 - 2015/12
N2 - KCa1.1 regulates smooth muscle contractility by modulating membrane potential, and age-associated changes in KCa1.1 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 KCa1.1 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 KCa1.1 and increased KCa1.1 currents, while no change was observed in KCa1.1 channel activity. The upregulation of KCa1.1 impaired intracellular Ca2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3-kinase, protein kinase Cζ, c-Jun N-terminal kinases, and nuclear factor kappa-B were found to be involved in KCa1.1 upregulation. Our findings suggest that age-associated changes in SL composition or CerS2 ablation upregulate KCa1.1 via the phosphoinositide 3-kinase/protein kinase Cζ/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.
AB - KCa1.1 regulates smooth muscle contractility by modulating membrane potential, and age-associated changes in KCa1.1 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 KCa1.1 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 KCa1.1 and increased KCa1.1 currents, while no change was observed in KCa1.1 channel activity. The upregulation of KCa1.1 impaired intracellular Ca2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3-kinase, protein kinase Cζ, c-Jun N-terminal kinases, and nuclear factor kappa-B were found to be involved in KCa1.1 upregulation. Our findings suggest that age-associated changes in SL composition or CerS2 ablation upregulate KCa1.1 via the phosphoinositide 3-kinase/protein kinase Cζ/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.
UR - http://www.scopus.com/inward/record.url?scp=84954364586&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/acel.12388
DO - https://doi.org/10.1111/acel.12388
M3 - مقالة
SN - 1474-9718
VL - 14
SP - 982
EP - 994
JO - Aging Cell
JF - Aging Cell
IS - 6
ER -