CaMKII is a novel regulator of diacylglycerol lipase-α and striatal endocannabinoid signaling

The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates activity-dependent depression of excitatory neurotransmission at central synapses; however, the molecular regulation of 2-AG synthesis is not well understood. Here we identify a novel functional interaction between the 2-AG synthetic enzyme diacylglycerol lipase-α (DGLα) and calcium/calmodulin dependent protein kinase II (CaMKII). Activated CaMKII interacts with the C-terminal domain of DGLα, phosphorylates two serine residues, and inhibits DGLα activity. Moreover, CaMKII inhibition augments short-term retrograde eCB signaling at striatal glutamatergic synapses. Consistent with an inhibitory role for CaMKII in synaptic 2-AG synthesis, in vivo genetic inhibition of CaMKII increases striatal DGL activity and basal 2-AG levels. Moreover, blockade of 2-AG breakdown using concentrations of JZL-184 that have no significant effect in wild type mice produces a hypo-locomotor response in mice with reduced CaMKII activity. These findings provide novel mechanistic insight into the molecular regulation of striatal eCB signaling with implications for physiological control of motor function.