Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling*
Sphingolipids are most prominently expressed in the plasma membrane, but recent studies have pointed to important signaling and regulatory roles in the nucleus. The most abundant nuclear sphingolipid is sphingomyelin (SM), which occurs in the nuclear envelope (NE) as well as intranuclear sites. The...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Elsevier
2008-06-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520423624 |
| _version_ | 1818726901154316288 |
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| author | Robert W. Ledeen Gusheng Wu |
| author_facet | Robert W. Ledeen Gusheng Wu |
| author_sort | Robert W. Ledeen |
| collection | DOAJ |
| description | Sphingolipids are most prominently expressed in the plasma membrane, but recent studies have pointed to important signaling and regulatory roles in the nucleus. The most abundant nuclear sphingolipid is sphingomyelin (SM), which occurs in the nuclear envelope (NE) as well as intranuclear sites. The major metabolic product of SM is ceramide, which is generated by nuclear sphingomyelinase and triggers apoptosis and other metabolic changes. Ceramide is further hydrolyzed to free fatty acid and sphingosine, the latter undergoing conversion to sphingosine phosphate by action of a specific nuclear kinase. Gangliosides are another type of sphingolipid found in the nucleus, members of the a-series of gangliotetraose gangliosides (GM1, GD1a) occurring in the NE and endonuclear compartments. GM1 in the inner membrane of the NE is tightly associated with a Na+/Ca2+ exchanger whose activity it potentiates, thereby contributing to regulation of Ca2+ homeostasis in the nucleus. This was shown to exert a cytoprotective role as absence or inactivation of this nuclear complex rendered cells vulnerable to apoptosis. This was demonstrated in the greatly enhanced kainite-induced seizure activity in knockout mice lacking gangliotetraose gangliosides. The pathology included apoptotic destruction of neurons in the CA3 region of the hippocampus. Ca2+ homeostasis was restored in these animals with LIGA-20, a membrane-permeant derivative of GM1 that entered the NE and activated the nuclear Na+/Ca2+ exchanger. Some evidence suggests the presence of uncharged glycosphingolipids in the nucleus. |
| first_indexed | 2024-12-17T22:05:34Z |
| format | Article |
| id | doaj.art-6b289cb86ff341bcaeb02ca38fe000b0 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T22:05:34Z |
| publishDate | 2008-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-6b289cb86ff341bcaeb02ca38fe000b02022-12-21T21:30:52ZengElsevierJournal of Lipid Research0022-22752008-06-0149611761186Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling*Robert W. Ledeen0Gusheng Wu1Department of Neurology & Neurosciences, New Jersey Medical School, The University of Medicine and Dentistry of New Jersey, Newark, NJ 07103Department of Neurology & Neurosciences, New Jersey Medical School, The University of Medicine and Dentistry of New Jersey, Newark, NJ 07103Sphingolipids are most prominently expressed in the plasma membrane, but recent studies have pointed to important signaling and regulatory roles in the nucleus. The most abundant nuclear sphingolipid is sphingomyelin (SM), which occurs in the nuclear envelope (NE) as well as intranuclear sites. The major metabolic product of SM is ceramide, which is generated by nuclear sphingomyelinase and triggers apoptosis and other metabolic changes. Ceramide is further hydrolyzed to free fatty acid and sphingosine, the latter undergoing conversion to sphingosine phosphate by action of a specific nuclear kinase. Gangliosides are another type of sphingolipid found in the nucleus, members of the a-series of gangliotetraose gangliosides (GM1, GD1a) occurring in the NE and endonuclear compartments. GM1 in the inner membrane of the NE is tightly associated with a Na+/Ca2+ exchanger whose activity it potentiates, thereby contributing to regulation of Ca2+ homeostasis in the nucleus. This was shown to exert a cytoprotective role as absence or inactivation of this nuclear complex rendered cells vulnerable to apoptosis. This was demonstrated in the greatly enhanced kainite-induced seizure activity in knockout mice lacking gangliotetraose gangliosides. The pathology included apoptotic destruction of neurons in the CA3 region of the hippocampus. Ca2+ homeostasis was restored in these animals with LIGA-20, a membrane-permeant derivative of GM1 that entered the NE and activated the nuclear Na+/Ca2+ exchanger. Some evidence suggests the presence of uncharged glycosphingolipids in the nucleus.http://www.sciencedirect.com/science/article/pii/S0022227520423624sphingolipidsphingomyelinsphingomyelinaseceramidesphingosine phosphategangliosides |
| spellingShingle | Robert W. Ledeen Gusheng Wu Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling* Journal of Lipid Research sphingolipid sphingomyelin sphingomyelinase ceramide sphingosine phosphate gangliosides |
| title | Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling* |
| title_full | Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling* |
| title_fullStr | Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling* |
| title_full_unstemmed | Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling* |
| title_short | Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling* |
| title_sort | thematic review series sphingolipids nuclear sphingolipids metabolism and signaling |
| topic | sphingolipid sphingomyelin sphingomyelinase ceramide sphingosine phosphate gangliosides |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520423624 |
| work_keys_str_mv | AT robertwledeen thematicreviewseriessphingolipidsnuclearsphingolipidsmetabolismandsignaling AT gushengwu thematicreviewseriessphingolipidsnuclearsphingolipidsmetabolismandsignaling |