title: CaMKII regulates diacylglycerol lipase-α and striatal endocannabinoid signaling.
abstract: The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates activity-dependent depression of excitatory neurotransmission at central synapses, but the molecular regulation of 2-AG synthesis is not well understood. Here we identify a functional interaction between the 2-AG synthetic enzyme diacylglycerol lipase-α (DGLα) and calcium/calmodulin dependent protein kinase II (CaMKII). Activated CaMKII interacted with the C-terminal domain of DGLα, phosphorylated two serine residues and inhibited DGLα activity. Consistent with an inhibitory role for CaMKII in 2-AG synthesis, in vivo genetic inhibition of CaMKII increased striatal DGL activity and basal levels of 2-AG, and CaMKII inhibition augmented short-term retrograde endocannabinoid signaling at striatal glutamatergic synapses. Lastly, blockade of 2-AG breakdown using concentrations of JZL-184 that have no effect in wild-type mice produced a hypolocomotor response in mice with reduced CaMKII activity. These findings provide mechanistic insights into the molecular regulation of striatal endocannabinoid signaling with implications for physiological control of motor function.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Shonesy
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Wang
authors.forename: Kristie L
authors.initials: KL
authors.lastname: Rose
authors.forename: Teniel S
authors.initials: TS
authors.lastname: Ramikie
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Cavener
authors.forename: Tyler
authors.initials: T
authors.lastname: Rentz
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baucum
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jalan-Sakrikar
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
authors.forename: Sachin
authors.initials: S
authors.lastname: Patel
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052117:Benzodioxoles / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D063388:Endocannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055785:Gene Knockdown Techniques / Q000379:methods; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010880:Piperidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; C094503:glyceryl 2-arachidonate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C480280:DAGLA protein, human; D008071:Lipoprotein Lipase