Diacylglycerol kinase epsilon regulates seizure susceptibility and long-term potentiation through arachidonoyl- inositol lipid signaling.

Abstract

Arachidonoyldiacylglycerol (20:4-DAG) is a second messenger derived from phosphatidylinositol 4,5-bisphosphate and generated by stimulation of glutamate metabotropic receptors linked to G proteins and activation of phospholipase C. 20:4-DAG signaling is terminated by its phosphorylation to phosphatidic acid, catalyzed by diacylglycerol kinase (DGK). We have cloned the murine DGKepsilon gene that showed, when expressed in COS-7 cells, selectivity for 20:4-DAG. The significance of DGKepsilon in synaptic function was investigated in mice with targeted disruption of the DGKepsilon. DGKepsilon(-/-) mice showed a higher resistance to electroconvulsive shock with shorter tonic seizures and faster recovery than DGKepsilon(+/+) mice. The phosphatidylinositol 4,5-bisphosphate-signaling pathway in cerebral cortex was greatly affected, leading to lower accumulation of 20:4-DAG and free 20:4. Also, long-term potentiation was attenuated in perforant path-dentate granular cell synapses. We propose that DGKepsilon contributes to modulate neuronal signaling pathways linked to synaptic activity, neuronal plasticity, and epileptogenesis.

• Authors: E B Rodriguez de Turco, W Tang, M K Topham, F Sakane, V L Marcheselli, C Chen, A Taketomi, S M Prescott, N G Bazan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 98 Issue 8 Pg. 4740-5 (Apr 10 2001) ISSN: 0027-8424 [Print] United States
• PMID: 11287665 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Arachidonic Acids
• DNA Primers
• Inositol
• Diacylglycerol Kinase

Topics

• Animals
• Arachidonic Acids (metabolism)
• Base Sequence
• Behavior, Animal
• DNA Primers
• Diacylglycerol Kinase (genetics, physiology)
• Female
• Hippocampus (physiopathology)
• Humans
• In Situ Hybridization
• In Vitro Techniques
• Inositol (analogs & derivatives, metabolism)
• Long-Term Potentiation (physiology)
• Male
• Mice
• Mice, Knockout
• Seizures (enzymology, physiopathology)
• Signal Transduction (physiology)