title: Receptor heteromerization expands the repertoire of cannabinoid signaling in rodent neurons.
abstract: A fundamental question in G protein coupled receptor biology is how a single ligand acting at a specific receptor is able to induce a range of signaling that results in a variety of physiological responses. We focused on Type 1 cannabinoid receptor (CB₁R) as a model GPCR involved in a variety of processes spanning from analgesia and euphoria to neuronal development, survival and differentiation. We examined receptor dimerization as a possible mechanism underlying expanded signaling responses by a single ligand and focused on interactions between CB₁R and delta opioid receptor (DOR). Using co-immunoprecipitation assays as well as analysis of changes in receptor subcellular localization upon co-expression, we show that CB₁R and DOR form receptor heteromers. We find that heteromerization affects receptor signaling since the potency of the CB₁R ligand to stimulate G-protein activity is increased in the absence of DOR, suggesting that the decrease in CB₁R activity in the presence of DOR could, at least in part, be due to heteromerization. We also find that the decrease in activity is associated with enhanced PLC-dependent recruitment of arrestin3 to the CB₁R-DOR complex, suggesting that interaction with DOR enhances arrestin-mediated CB₁R desensitization. Additionally, presence of DOR facilitates signaling via a new CB₁R-mediated anti-apoptotic pathway leading to enhanced neuronal survival. Taken together, these results support a role for CB₁R-DOR heteromerization in diversification of endocannabinoid signaling and highlight the importance of heteromer-directed signal trafficking in enhancing the repertoire of GPCR signaling.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Raphael
authors.initials: R
authors.lastname: Rozenfeld
authors.forename: Ittai
authors.initials: I
authors.lastname: Bushlin
authors.forename: Ivone
authors.initials: I
authors.lastname: Gomes
authors.forename: Nikos
authors.initials: N
authors.lastname: Tzavaras
authors.forename: Achla
authors.initials: A
authors.lastname: Gupta
authors.forename: Susana
authors.initials: S
authors.lastname: Neves
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Battini
authors.forename: G Luca
authors.initials: GL
authors.lastname: Gusella
authors.forename: Alexander
authors.initials: A
authors.lastname: Lachmann
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blitzer
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
mesh_terms: D000818:Animals; D017209:Apoptosis; D019390:Arrestins / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D002540:Cerebral Cortex / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry* / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019390:Arrestins; D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D017465:Receptors, Opioid, delta; C082333:arrestin3; D048049:Extracellular Signal-Regulated MAP Kinases