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The Journal of Neuroscience, March 22, 2006, 26(12):3141-3153; doi:10.1523/JNEUROSCI.5437-05.2006
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Cellular/Molecular
Constitutive Activation Drives Compartment-Selective Endocytosis and Axonal Targeting of Type 1 Cannabinoid Receptors
Christophe Leterrier,1 Jeanne Lainé,2 Michèle Darmon,3 Hélène Boudin,4 Jean Rossier,1 andZsolt Lenkei1 1Laboratoire Neurobiologie et Diversité Cellulaire, Ecole Supérieure de Physique et de Chimie Industrielles-Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7637, 75013 Paris, France, 2Laboratoire de Neurobiologie du Cervelet, Université Pierre et Marie Curie Paris 6, Faculté de Médecine Pitié Salpêtrière, 75013 Paris, France, 3Neuropsychopharmacologie, Université Pierre et Marie Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 677, Faculté de Médecine Pitié Salpêtrière, 75013 Paris, France, and 4Equipe Mixte INSERM 0350, Hôpital Saint Antoine, 75012 Paris, France
Correspondence should be addressed to Dr. Zsolt Lenkei, Laboratoire Neurobiologie et Diversité Cellulaire, Ecole Supérieure de Physique et de Chimie Industrielles–Centre National de la Recherche Scientifique Unité Mixte de Recherche 7637, 10 rue Vauquelin, 75231 Paris, Cedex 05, France. Email: zsolt.lenkei{at}espci.fr
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.
Key words: constitutive activity; inverse agonist; targeting; plasma membrane; GPCR; axon
Received Sept. 15, 2005; revised Jan. 27, 2006; accepted Jan. 28, 2006.
Correspondence should be addressed to Dr. Zsolt Lenkei, Laboratoire Neurobiologie et Diversité Cellulaire, Ecole Supérieure de Physique et de Chimie Industrielles–Centre National de la Recherche Scientifique Unité Mixte de Recherche 7637, 10 rue Vauquelin, 75231 Paris, Cedex 05, France. Email: zsolt.lenkei{at}espci.fr
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