Diacylglycerol kinase epsilon regulates seizure susceptibility and long-term potentiation through arachidonoyl- inositol lipid signaling.
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.
Rodriguez de Turco
E B
EB
Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Tang
W
W
Topham
M K
MK
Sakane
F
F
Marcheselli
V L
VL
Chen
C
C
Taketomi
A
A
Prescott
S M
SM
Bazan
N G
NG
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001483:Base Sequence; D001522:Behavior, Animal; D017931:DNA Primers; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007294:Inositol / Q000031:analogs & derivatives / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012640:Seizures / Q000201:enzymology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*
D001095:Arachidonic Acids; D017931:DNA Primers; D007294:Inositol; D019852:Diacylglycerol Kinase