title: GPR37 protein trafficking to the plasma membrane regulated by prosaposin and GM1 gangliosides promotes cell viability.
abstract: The subcellular distribution of the G protein-coupled receptor GPR37 affects cell viability and is implicated in the pathogenesis of parkinsonism. Intracellular accumulation and aggregation of GPR37 cause cell death, whereas GPR37 located in the plasma membrane provides cell protection. We define here a pathway through which the recently identified natural ligand, prosaposin, promotes plasma membrane association of GPR37. Immunoabsorption of extracellular prosaposin reduced GPR37(tGFP) surface density and decreased cell viability in catecholaminergic N2a cells. We found that GPR37(tGFP) partitioned in GM1 ganglioside-containing lipid rafts in the plasma membrane of live cells. This partitioning required extracellular prosaposin and was disrupted by lipid raft perturbation using methyl-β-cyclodextrin or cholesterol oxidase. Moreover, complex formation between GPR37(tGFP) and the GM1 marker cholera toxin was observed in the plasma membrane. These data show functional association between GPR37, prosaposin, and GM1 in the plasma membrane. These results thus tie together the three previously defined components of the cellular response to insult. Our findings identify a mechanism through which the receptor's natural ligand and GM1 may protect against toxic intracellular GPR37 aggregates observed in parkinsonism.
authors.affiliation: From the Laboratory of Translational Neuropharmacology and.
authors.forename: Ebba Gregorsson
authors.initials: EG
authors.lastname: Lundius
authors.forename: Vladana
authors.initials: V
authors.lastname: Vukojevic
authors.forename: Ellen
authors.initials: E
authors.lastname: Hertz
authors.forename: Nikolas
authors.initials: N
authors.lastname: Stroth
authors.forename: Andreas
authors.initials: A
authors.lastname: Cederlund
authors.forename: Masao
authors.initials: M
authors.lastname: Hiraiwa
authors.forename: Lars
authors.initials: L
authors.lastname: Terenius
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D016764:Cell Polarity / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D005434:Flow Cytometry; D036681:Fluorescence Recovery After Photobleaching; D005677:G(M1) Ganglioside / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D049231:Saposins / Q000378:metabolism*; D013997:Time Factors; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: C509804:Gpr37 protein, mouse; D009414:Nerve Growth Factors; D010455:Peptides; C483344:Psap protein, mouse; D043562:Receptors, G-Protein-Coupled; D049231:Saposins; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C101246:prosaptide; D049452:Green Fluorescent Proteins; D005677:G(M1) Ganglioside
keywords: Fluorescence Correlation Spectroscopy; G Protein-coupled Receptors (GPCR); Ganglioside; Lipid Raft; Pael-R; Parkinson Disease