title: Activation-dependent plasticity of polarized GPCR distribution on the neuronal surface.
abstract: Directionality of information flow through neuronal networks is sustained at cellular level by polarized neurons. However, specific targeting or anchoring motifs responsible for polarized distribution on the neuronal surface have only been identified for a few neuronal G-protein-coupled receptors (GPCRs). Here, through mutational and pharmacological modifications of the conformational state of two model GPCRs, the axonal CB1R cannabinoid and the somatodendritic SSTR2 somatostatin receptors, we show important conformation-dependent variations in polarized distribution. The underlying mechanisms include lower efficiency of conformation-dependent GPCR endocytosis in axons, compared with dendrites, particularly at moderate activation levels, as well as endocytosis-dependent transcytotic delivery of GPCRs from the somatodendritic domain to distal axonal portions, shown by using compartmentalized microfluidic devices. Kinetic modeling predicted that GPCR distribution polarity is highly regulated by steady-state endocytosis, which is conformation dependent and is able to regulate the relative amount of GPCRs targeted to axons and that axonally polarized distribution is an intermediary phenotype that appears at moderate basal activation levels. Indeed, we experimentally show that gradual changes in basal activation-dependent endocytosis lead to highly correlated shifts of polarized GPCR distribution on the neuronal surface, which can even result in a fully reversed polarized distribution of naturally somatodendritic or axonal GPCRs. In conclusion, polarized distribution of neuronal GPCRs may have a pharmacologically controllable component, which, in the absence of dominant targeting motifs, could even represent the principal regulator of sub-neuronal distribution. Consequently, chronic modifications of basal GPCR activation by therapeutic or abused drugs may lead to previously unanticipated changes in brain function through perturbation of polarized GPCR distribution on the neuronal surface.
authors.affiliation: Laboratoire de Neurobiologie, CNRS UMR7637, ESPCI-ParisTech, 10 Rue Vauquelin, Paris 75005, France.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Simon
authors.forename: Claude
authors.initials: C
authors.lastname: Loverdo
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Gaffuri
authors.forename: Michel
authors.initials: M
authors.lastname: Urbanski
authors.forename: Delphine
authors.initials: D
authors.lastname: Ladarre
authors.forename: Damien
authors.initials: D
authors.lastname: Carrel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rivals
authors.forename: Christophe
authors.initials: C
authors.lastname: Leterrier
authors.forename: Olivier
authors.initials: O
authors.lastname: Benichou
authors.forename: Pascal
authors.initials: P
authors.lastname: Dournaud
authors.forename: Bela
authors.initials: B
authors.lastname: Szabo
authors.forename: Raphael
authors.initials: R
authors.lastname: Voituriez
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Lenkei
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D016764:Cell Polarity; D003712:Dendrites / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D046210:Microfluidic Analytical Techniques; D008954:Models, Biological; D009415:Nerve Net / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D017481:Receptors, Somatostatin / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D015183:Restriction Mapping
chemical_list: D020033:Protein Isoforms; D043884:Receptor, Cannabinoid, CB1; D017481:Receptors, Somatostatin; C115977:Sstr2 protein, rat
keywords: constitutive; diffusion; endocytosis; internalization; targeting; transcytosis