The Cannabinoid Receptor CB1 Interacts with the WAVE1 Complex and Plays a Role in Actin Dynamics and Structural Plasticity in Neurons

• Published in: PLoS biology 2015-10, Vol.13 (10), p.e1002286-e1002286
• Main Authors: Njoo, Christian, Agarwal, Nitin, Lutz, Beat, Kuner, Rohini
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - drug effects; Actin Cytoskeleton - metabolism; Animals; Cannabinoids - pharmacology; Cells, Cultured; Cercopithecus aethiops; COS Cells; Dendritic Spines - drug effects; Dendritic Spines - metabolism; Embryo, Mammalian - cytology; Experiments; Frontal Lobe - cytology; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Graphs; Growth Cones - drug effects; Growth Cones - metabolism; Kinases; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle proteins; Nerve Tissue Proteins - agonists; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nervous system; Neurogenesis - drug effects; Neuronal Plasticity - drug effects; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Pain; Parietal Lobe - cytology; Parietal Lobe - drug effects; Parietal Lobe - metabolism; Physiological aspects; Physiology; Polymerization; Proteins; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Studies; Wiskott-Aldrich Syndrome Protein, Neuronal - metabolism
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1002286

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.