CaMKII regulates diacylglycerol lipase-α and striatal endocannabinoid signaling.

Shonesy BC, Wang X, Rose KL, Ramikie TS, Cavener VS, Rentz T, Baucum AJ, Jalan-Sakrikar N, Mackie K, Winder DG, Patel S, Colbran RJ
Nat Neurosci. 2013 16 (4): 456-63

PMID: 23502535 · PMCID: PMC3636998 · DOI:10.1038/nn.3353

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.

MeSH Terms (17)

Animals Arachidonic Acids Benzodioxoles Calcium-Calmodulin-Dependent Protein Kinase Type 2 Corpus Striatum Endocannabinoids Gene Knockdown Techniques Glycerides HEK293 Cells Humans Lipoprotein Lipase Male Mice Mice, Inbred C57BL Mice, Transgenic Piperidines Signal Transduction

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