The role of ceramide in cell signaling

Perry, David K.; Hannun, Yusuf A.

doi:10.1016/s0005-2760(98)00145-3

Cited by 301 publications

(227 citation statements)

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“…3-oxosphinganine is subsequently reduced to dihydrosphingosine, then acylated by ceramide synthase to yield dihydroceramide and oxidized to yield ceramide by the introduction of a trans-4, 5 double bond by dihydroceramide reductase [8]. This pathway can be stimulated by DNA-damaging substances such as daunorubicin or radiation and requires several hours for the generation of detectable ceramide [3], [7], [9]. Ceramide may also be produced via the action of several distinct enzymes involved in the cleavage of SM, namely acidic (a) and neutral (n) sphingomyelienases (aSMase and nSMase, respectively), which have been characterized based on their pH-optima and biological effects [10].…”

Section: Sm Metabolism and Generation Of Ceramidementioning

confidence: 99%

“…Acid SMase in both humans and mice have been cloned and determined to be the product of a conserved gene [13]. The aSMase protein is generated as a 75 kDa precursor which is processed to a final species of 70 and/or 57 kDa [3], [8], [14], [15]. An acidic environment enhances the catalytic activity of aSMase, but is not absolutely required for its function.…”

Section: Sm Metabolism and Generation Of Ceramidementioning

confidence: 99%

“…Although still an elusive class of lipids, studies on the involvement of sphingolipids in signaling pathways that mediate cell growth, differentiation, cell death and multiple cell functions have been quickly expanding our comprehension of these compounds. In addition to many newly discovered roles of ceramide as an intracellular second messenger for the receptors of tumor necrosis factor-alpha (TNF-α), IL-1-β, and other cytokines, sphingosine, sphingosine-1-phosphate, and other sphingolipid metabolites have recently been demonstrated to modulate cell proliferation and cellular calcium homeostasis [2,3] Enzymatic degradation of sphingolipids like sphingomyelin (N-acylsphongosin-1-phosphorylcholine; SM) is one of the major mechanisms for the generation of smaller lipid messengers. An important constituent of SM breakdown is ceramide, a second messenger generated in a plethora of signaling cascades [3].…”

mentioning

confidence: 99%

“…In addition to many newly discovered roles of ceramide as an intracellular second messenger for the receptors of tumor necrosis factor-alpha (TNF-α), IL-1-β, and other cytokines, sphingosine, sphingosine-1-phosphate, and other sphingolipid metabolites have recently been demonstrated to modulate cell proliferation and cellular calcium homeostasis [2,3] Enzymatic degradation of sphingolipids like sphingomyelin (N-acylsphongosin-1-phosphorylcholine; SM) is one of the major mechanisms for the generation of smaller lipid messengers. An important constituent of SM breakdown is ceramide, a second messenger generated in a plethora of signaling cascades [3]. Deregulation in intracellular ceramide levels is believed to be involved in many diseases such as diabetes, AIDS, neurodegenerative disorders, and autoimmunity [4].…”

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confidence: 99%

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The yins and yangs of ceramide

Sharma

Shi

1999

Cell Res

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Since their discovery over 100 years ago, sphingolipids have caught the eyes and the imagination of scientists. Modern science has made many new insights on the cell biology and day-to-day functions of many integral sphingolipids, especially those of ceramide. Ceramide is recognized as a vital second messenger in the signal transduction process mediated by receptors of many cytokines and growth factors. A great part of our current understanding of ceramide has been achieved from apoptosis-related studies, however recent data in the fields of immunology, endocrinology and neurobiology, also suggest a fundamental involvement of ceramide in the onset of diseases. Therefore, understanding the biology of ceramide could be a key to unraveling many biological mechanisms and provide information for the treatment of some common diseases.

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Section: Sm Metabolism and Generation Of Ceramidementioning

confidence: 99%

Section: Sm Metabolism and Generation Of Ceramidementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The yins and yangs of ceramide

Sharma

Shi

1999

Cell Res

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“…Ceramides can also be formed by the degradation of complex SLs, such as sphingomyelin or glycosphingolipids. Ceramides can function as a second messenger in a variety of cellular events, including apoptosis and differentiation (Perry & Hannun, 1998; Gulbins, 2003), and the effects of ceramides may vary according to its acyl chain length (Mesicek et al ., 2010). However, little is known about whether the aging process alters SL composition in cells and thereby affects ion channels to cause gastrointestinal motility disorder.…”

Section: Introductionmentioning

confidence: 99%

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaK_C_a1.1 upregulation

Choi

Kim

et al. 2015

Aging Cell

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Summary KC a1.1 regulates smooth muscle contractility by modulating membrane potential, and age‐associated changes in KC a1.1 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 KC a1.1 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 KC a1.1 and increased KC a1.1 currents, while no change was observed in KC a1.1 channel activity. The upregulation of KC a1.1 impaired intracellular 2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3‐kinase, protein kinase C ζ, c‐Jun N‐terminal kinases, and nuclear factor kappa‐B were found to be involved in KC a1.1 upregulation. Our findings suggest that age‐associated changes in SL composition or CerS2 ablation upregulate KC a1.1 via the phosphoinositide 3‐kinase/protein kinase C ζ/c‐Jun N‐terminal kinases/nuclear factor kappa‐B‐mediated pathway and impair 2+ 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.

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CDP-choline: Neuroprotection in transient forebrain ischemia of gerbils

1999

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CDP‐choline is a rate‐limiting intermediate in the biosynthesis of phosphatidylcholine (PtdCho), an important component of the neural cell membrane. The ability of CDP‐choline to alter phospholipid metabolism is an important function in the treatment of ischemic injury. Exogenous treatment with CDP‐choline stimulates PtdCho synthesis and prevents release of free fatty acids (FFA), especially arachidonic acid (AA), after ischemia/reperfusion. Phase III clinical trials of CDP‐choline in the treatment of stroke are currently underway. Here we report the neuroprotection by CDP‐choline in transient forebrain ischemia of gerbils. CDP‐choline significantly attenuated the blood‐brain barrier (BBB) dysfunction after ischemia with 6‐hr reperfusion, and considerably reduced the increase of AA in FFA and leukotriene C4 (LTC4) synthesis at 1 day. Edema was significantly elevated after 1 and 2 days, but attained maximum at 3‐day reperfusion. CDP‐choline substantially attenuated edema at 3 days. Ischemia resulted in 80 ± 8% CA1 hippocampal neuronal death after 6‐day reperfusion, and CDP‐choline provided 65 ± 6% neuroprotection. CDP‐choline may act by increasing PtdCho synthesis via two pathways: (1) conversion of 1,2‐diacylglycerol to PtdCho, and (2) biosynthesis of S‐adenosyl‐L‐methionine, thus stabilizing the membrane and reducing AA release and metabolism to leukotriene C4. This would result in decreased toxicity due to AA, leukotrienes, oxygen radicals, lipid peroxidation, and altered glutamate uptake, thus limiting BBB dysfunction, edema and providing neuroprotection. J. Neurosci. Res. 58:697–705, 1999. © 1999 Wiley‐Liss, Inc.

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The role of ceramide in cell signaling

Cited by 301 publications

References 102 publications

The yins and yangs of ceramide

The yins and yangs of ceramide

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaK_C_a1.1 upregulation

CDP-choline: Neuroprotection in transient forebrain ischemia of gerbils

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The role of ceramide in cell signaling

Cited by 301 publications

References 102 publications

The yins and yangs of ceramide

The yins and yangs of ceramide

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaKCa1.1 upregulation

CDP-choline: Neuroprotection in transient forebrain ischemia of gerbils

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Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaK_C_a1.1 upregulation