Abstract
The molecular composition of the cannabinoid type 1 (CB1) receptor complex beyond the classical G-protein signaling components is not known. Using proteomics on mouse cortex in vivo, we pulled down proteins interacting with CB1 in neurons and show that the CB1 receptor assembles with multiple members of the WAVE1 complex and the RhoGTPase Rac1 and modulates their activity. Activation levels of CB1 receptor directly impacted on actin polymerization and stability via WAVE1 in growth cones of developing neurons, leading to their collapse, as well as in synaptic spines of mature neurons, leading to their retraction. In adult mice, CB1 receptor agonists attenuated activity-dependent remodeling of dendritic spines in spinal cord neurons in vivo and suppressed inflammatory pain by regulating the WAVE1 complex. This study reports novel signaling mechanisms for cannabinoidergic modulation of the nervous system and demonstrates a previously unreported role for the WAVE1 complex in therapeutic applications of cannabinoids.
Fig 1. CB1 physically interacts with members of the WAVE1 signaling complex in mouse brain and colocalizes with WAVE1 in neurons.

Fig 2. Increased localization of colocalization of WAVE1 and CB1-EGFP at the cell membrane in heterologously-transfected COS7 cells upon ACEA treatment.

Fig 3. Cannabinoids directly modulate Rac1 activity and WAVE1 phosphorylation by Rac1 Activation and WAVE1 Phosphorylation via CB1.

Fig 4. Visualization of cannabinoidergic modulation of actin dynamics in neuronal growth cones mediated by CB1 and WAVE1.

Fig 5. Cannabinoids regulate growth cone morphology via CB1-Gi-Rac1-WAVE1 signaling.

Fig 6. CB1 receptor is expressed in axonal as well as dendritic compartments of primary neurons matured over 4 wk in vitro.

Fig 7. Visualization of disassembly of F-actin by cannabinoid agonists in in dendritic spines on mature cortical neurons, leading to reduction in the density of mature spines.

Fig 8. Intrathecal delivery of ACEA inhibits mechanical nociceptive hypersensitivity and nociceptive activity-induced structural plasticity of dendrites on spinal dorsal horn neurons in inflammatory pain conditions in vivo.

Fig 9. Role of spinally-expressed WAVE1 in nociceptive activity-induced structural plasticity, inflammatory pain, and cannabinoidergic analgesia in vivo.
Source: https://pubmed.ncbi.nlm.nih.gov/26496209 October 2015