Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via K(Ca) 1.1 upregulation.
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 KC a 1.1 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 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 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.
Department of Physiology, Medical School, Ewha Womans University, Seoul, Korea.
Shinkyu
S
Choi
Department of Physiology, Medical School, Ewha Womans University, Seoul, Korea.
Ji Aee
JA
Kim
Department of Internal Medicine, Medical School, Ewha Womans University, Seoul, Korea.
Tae Hun
TH
Kim
Department of Physiology, Medical School, Ewha Womans University, Seoul, Korea.
Hai-Yan
HY
Li
College of Pharmacy and MRC, Chungbuk National University, Chongju, Korea.
Kyong-Oh
KO
Shin
College of Pharmacy and MRC, Chungbuk National University, Chongju, Korea.
Yong-Moon
YM
Lee
Department of Molecular Medicine, Medical School, Ewha Womans University, Seoul, Korea.
Seikwan
S
Oh
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Yael
Y
Pewzner-Jung
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Anthony H
AH
Futerman
Department of Physiology, Medical School, Ewha Womans University, Seoul, Korea.
Suk Hyo
SH
Suh
D000375:Aging / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism*; D051049:Sphingosine N-Acyltransferase / Q000235:genetics; D013270:Stomach / Q000473:pathology; D015533:Transcriptional Activation
D002518:Ceramides; D051036:Large-Conductance Calcium-Activated Potassium Channels; D016328:NF-kappa B; D034741:RNA, Small Interfering; D013107:Sphingolipids; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C
Ca2+-activated K+ channel; aging; ceramide synthases; contractile dysfunction; smooth muscle; sphingolipids