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.
Highlights
Psychoactive cannabinoids derived from marijuana as well as diverse endocannabinoids, such as anandamide and 2-arachidonylglycerol (2-AG) bind to and activate signaling via cannabinoid type 1 and type 2 (CB1 and cannabinoid type 2 receptor (CB2)) receptors, which belong to the G-protein coupled receptor (GPCR) family
We identify the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein 1 (WAVE1)-complex—known to be involved in actin nucleation —as novel interacting partners of CB1R
We observe a functional relationship between the WAVE1-complex and CB1R in the regulation of actin filaments in developing as well as PLOS Biology | DOI:10.1371/journal.pbio
Summary
Psychoactive cannabinoids derived from marijuana as well as diverse endocannabinoids, such as anandamide and 2-arachidonylglycerol (2-AG) bind to and activate signaling via cannabinoid type 1 and type 2 (CB1 and CB2) receptors, which belong to the G-protein coupled receptor (GPCR) family. Gene deletion studies have uncovered the tremendous significance of the CB1 receptor in mediating several key biological functions of (endo)cannabinoids in the adult central nervous system (CNS), including learning and memory, pain and analgesia, neuronal excitability and seizures, fear acquisition and extinction, and appetite control, amongst several others [1,2,3]. Cell type-specific CB1 receptor knockout mice have revealed key roles for CB1 receptor expressed in excitatory neurons in appetite, neuroprotection, epilepsy, fear, anxiety, pain, and analgesia, amongst others [6,7,8,9,10]. Recent studies have shown that far from enfolding their functions in the adult nervous system alone, endocannabinoids are important regulators of neuronal development; the CB1 receptor has been implicated in collapse and navigation of axonal growth cones in inhibitory as well as excitatory neurons [11,12,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
