Journal
NATURE NEUROSCIENCE
Volume 16, Issue 4, Pages 456-U124Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3353
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Funding
- US National Institutes of Health [T32-NS007491, T32-MH065215, K01-NS073700, K05-DA021696, R01-DA011322, R01-AA019455, K08-MH090412, R01-MH063232, R01-NS078291]
- Michael J. Fox Foundation
- Luton Society
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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-alpha (DGL alpha) and calcium/calmodulin dependent protein kinase II (CaMKII). Activated CaMKII interacted with the C-terminal domain of DGL alpha, phosphorylated two serine residues and inhibited DGL alpha 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.
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