- 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. CaMKII regulates diacylglycerol lipase-α and striatal endocannabinoid signaling. Nature neuroscience. 2013 Apr;16(4). 456-63. PMID: 23502535 [PubMed]. PMCID: PMC3636998. NIHMSID: NIHMS445833.
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.