Synaptic removal of diacylglycerol by DGKzeta and PSD-95 regulates dendritic spine maintenance.
Diacylglycerol (DAG) is an important lipid signalling molecule that exerts an effect on various effector proteins including protein kinase C. A main mechanism for DAG removal is to convert it to phosphatidic acid (PA) by DAG kinases (DGKs). However, it is not well understood how DGKs are targeted to specific subcellular sites and tightly regulates DAG levels. The neuronal synapse is a prominent site of DAG production. Here, we show that DGKzeta is targeted to excitatory synapses through its direct interaction with the postsynaptic PDZ scaffold PSD-95. Overexpression of DGKzeta in cultured neurons increases the number of dendritic spines, which receive the majority of excitatory synaptic inputs, in a manner requiring its catalytic activity and PSD-95 binding. Conversely, DGKzeta knockdown reduces spine density. Mice deficient in DGKzeta expression show reduced spine density and excitatory synaptic transmission. Time-lapse imaging indicates that DGKzeta is required for spine maintenance but not formation. We propose that PSD-95 targets DGKzeta to synaptic DAG-producing receptors to tightly couple synaptic DAG production to its conversion to PA for the maintenance of spine density.
Kim
Karam
K
National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Yuseong-gu, Daejeon, Republic of Korea.
Yang
Jinhee
J
Zhong
Xiao-Ping
XP
Kim
Myoung-Hwan
MH
Kim
Yun Sook
YS
Lee
Hyun Woo
HW
Han
Seungnam
S
Choi
Jeonghoon
J
Han
Kihoon
K
Seo
Jinsoo
J
Prescott
Stephen M
SM
Topham
Matthew K
MK
Bae
Yong Chul
YC
Koretzky
Gary
G
Choi
Se-Young
SY
Kim
Eunjoon
E
D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*
D004075:Diglycerides; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; C526463:DGKZ protein, human; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; C508008:diacylglycerol kinase zeta, rat; D011493:Protein Kinase C; D051528:Guanylate Kinases