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

Christian Njoo; Nitin Agarwal; Beat Lutz; Rohini Kuner

doi:10.1371/journal.pbio.1002286

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

PLoS Biol. 2015 Oct 23;13(10):e1002286. doi: 10.1371/journal.pbio.1002286. eCollection 2015 Oct.

Authors

Christian Njoo¹, Nitin Agarwal¹, Beat Lutz², Rohini Kuner¹

Affiliations

¹ Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
² Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Cytoskeleton / drug effects
Actin Cytoskeleton / metabolism*
Animals
COS Cells
Cannabinoids / pharmacology
Cells, Cultured
Chlorocebus aethiops
Dendritic Spines / drug effects
Dendritic Spines / metabolism
Embryo, Mammalian / cytology
Frontal Lobe / cytology
Frontal Lobe / drug effects
Frontal Lobe / metabolism*
Growth Cones / drug effects
Growth Cones / metabolism
Luminescent Proteins / genetics
Luminescent Proteins / metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins / agonists
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neurogenesis / drug effects
Neuronal Plasticity* / drug effects
Neurons / cytology
Neurons / drug effects
Neurons / metabolism*
Parietal Lobe / cytology
Parietal Lobe / drug effects
Parietal Lobe / metabolism*
Receptor, Cannabinoid, CB1 / agonists
Receptor, Cannabinoid, CB1 / genetics
Receptor, Cannabinoid, CB1 / metabolism*
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / metabolism
Wiskott-Aldrich Syndrome Protein, Neuronal / metabolism*

Substances

CNR1 protein, mouse
Cannabinoids
Luminescent Proteins
Nerve Tissue Proteins
Receptor, Cannabinoid, CB1
Recombinant Fusion Proteins
Wasl protein, mouse
Wiskott-Aldrich Syndrome Protein, Neuronal

Grants and funding

This work was supported by grants to RK from the European Research Council (ERC) Advanced Investigator project number 294293 and the collaborative research center 1158 (SFB 1158) of the Deutsche Forschungsgemeinschaft. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.