ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2006
Constitutive activation drives compartment-selective endocytosis and axonal targeting of type 1 cannabinoid receptors.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 201 citations in OpenAlex.
- Phase 2, open-label INSPIRE trial to assess the tolerability and effectiveness of transdermal cannabidiol gel in children and adolescents with 22q11.2 deletion syndrome (ZYN2-CL-031).Journal of neurodevelopmental disorders · 2026Trial
- Cannabinoid tolerance relies on CBProceedings of the National Academy of Sciences of the United States of America · 2026Article
- From localization to function: comparative analysis of CB1 in sperm across species and its epigenetic role in humans.Cell death & disease · 2026Article
- Canonical Cannabinoid Receptors.Current topics in behavioral neurosciences · 2026Review
- Cannabinoids: Role in Neurological Diseases and Psychiatric Disorders.International journal of molecular sciences · 2024Review
- Review
- SGIP1 binding to the α-helical H9 domain of cannabinoid receptor 1 promotes axonal surface expression.Journal of cell science · 2024Article
- Presynaptic nanoscale components of retrograde synaptic signaling.Science advances · 2024Article
- Local glycolysis fuels actomyosin contraction during axonal retraction.The Journal of cell biology · 2023Article
- Location-biased activation of the proton-sensor GPR65 is uncoupled from receptor trafficking.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Compartment-Specific Activation of the Proton-Sensor GPR65 is Uncoupled from Receptor Trafficking.bioRxiv : the preprint server for biology · 2023Article
- SGIP1 in axons prevents internalization of desensitized CB1R and modifies its function.Frontiers in neuroscience · 2023Review
- Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3.The Journal of cell biology · 2022Article
- Spatial regulation of endosomes in growing dendrites.Developmental biology · 2022Review
- Imaging the endocannabinoid signaling system.Journal of neuroscience methods · 2022Review
- The incidence of candidate binding sites for β-arrestin in Drosophila neuropeptide GPCRs.PloS one · 2022Article
- Nanoscale Sub-Compartmentalization of the Dendritic Spine Compartment.Biomolecules · 2021Review
- Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling.EMBO molecular medicine · 2020Article
- Spatial control of membrane traffic in neuronal dendrites.Molecular and cellular neurosciences · 2020Review
- Kinesin-1-mediated axonal transport of CB1 receptors is required for cannabinoid-dependent axonal growth and guidance.Development (Cambridge, England) · 2020Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The type 1 cannabinoid receptor (CB1R) is one of the most abundant G-protein-coupled receptors (GPCRs) in the brain, predominantly localized to axons of GABAergic neurons. Like several other neuronal GPCRs, CB1R displays significant in vitro constitutive activity (i.e., spontaneous activation in the absence of ligand). However, a clear biological role for constitutive GPCR activity is still lacking. This question was addressed by studying the consequences of constitutive activation on the intracellular trafficking of endogenous or transfected CB1Rs in cultured hippocampal neurons using optical and electron microscopy. We found that constitutive activity results in a permanent cycle of endocytosis and recycling, which is restricted to the somatodendritic compartment. Thus, CB1Rs are continuously removed by endocytosis from the plasma membrane in the somatodendritic compartment but not in axons, where CB1Rs accumulate on surface. Blocking constitutive activity by short-term incubation with inverse agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281) results in sequestration of recycled CB1Rs on the somatodendritic plasma membrane. Long-term inhibition of endocytosis by cotransfection of dominant-negative proteins results in impaired axonal polarization of surface-bound CB1Rs. Kinetic analysis shows that the majority of newly synthesized CB1Rs arrive first to the somatodendritic plasma membrane, from where they are rapidly removed by AM281-sensitive constitutive endocytosis before being delivered to axons. Thus, constitutive-activity driven somatodendritic endocytosis is required for the proper axonal targeting of CB1R, representing a novel, conformation-dependent targeting mechanism for axonal GPCRs.
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