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; 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.

The initiation of synaptic 2-AG mobilization requires both an increased supply of diacylglycerol precursor and increased postsynaptic calcium

“…1b,c p>0.05 by one-sample t-test). This concentration of DHPG is able to augment 2-AG mobilization when combined with brief postsynaptic depolarization (Shonesy et al, 2013). These data suggest that SAG is not converted to an active synaptic pool of 2-AG under these basal conditions and that the main role of mGluR activation is to stimulate production of DAG.…”

“…Accordingly, multiple behavioral studies have demonstrated the importance of endocannabinoid signaling in a variety of physiological functions (Fernandez-Ruiz and Gonzales, 2005; Marsicano et al, 2002; Orio et al, 2009; Patel et al, 2009; Varvel and Lichtman, 2002). On-demand, postsynaptic synthesis and release of endocannabinoids can induce short (Kreitzer and Regehr, 2001; Shonesy et al, 2013) or long-term depression of transmitter release (Gerdeman et al, 2002; Lerner et al, 2010; Lerner and Kreitzer, 2012) through activation of presynaptic type 1 cannabinoid receptors (CB1Rs) (El Manira and Kyriakatos, 2010; Heifets and Castillo, 2009). …”

Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways

“…The stimulation of single MSNs by depolarizing pulses or action potential trains ( fig. S1), which trigger endocannabinoid (eCB) release (9)(10)(11)(12), induced a transient depression (76.5 ± 2.9% relative to the control EPSC amplitude, P < 0.001) in 16 out of 33 homoneuronal synapses (48.5%) (Fig. 1, B and C).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Similar Purkinje neuron depolarization also suppresses the GABAergic synapses from cerebellar cortical interneurons (Tanimura et al, 2010), such as the GABAergic basket cells (Szabo et al, 2004). In addition to the HC and cerebellum, DSI and/or DSE is also observed, e.g., in the VTA DA neurons (Melis et al, 2004), NAc MSNs (Tanimura et al, 2010;Shonesy et al, 2013), and in the BLA neurons (Zhu and Lovinger, 2005;Yoshida et al, 2011;Shonesy et al, 2014). Together these findings suggest that the retrograde eCB signaling is a very general "local" transient process that tunes neurotransmission (reviewed in Wilson and Nicoll, 2002;Kano et al, 2009).…”