title: Rab8 modulates metabotropic glutamate receptor subtype 1 intracellular trafficking and signaling in a protein kinase C-dependent manner.
abstract: Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) that are activated by glutamate, the primary excitatory neurotransmitter in the CNS. Alterations in glutamate receptor signaling are implicated in neuropathologies such as Alzheimer's disease, ischemia, and Huntington's disease among others. Group 1 mGluRs (mGluR1 and mGluR5) are primarily coupled to Gα(q/11) leading to the activation of phospholipase C and the formation of diacylglycerol and inositol 1,4,5-trisphosphate, which results in the release of intracellular calcium stores and protein kinase C (PKC) activation. Desensitization, endocytosis, and recycling are major mechanisms of GPCR regulation, and the intracellular trafficking of GPCRs is linked to the Rab family of small G proteins. Rab8 is a small GTPase that is specifically involved in the regulation of secretory/recycling vesicles, modulation of the actin cytoskeleton, and cell polarity. Rab8 has been shown to regulate the synaptic delivery of AMPA receptors during long-term potentiation and during constitutive receptor recycling. We show here that Rab8 interacts with the C-terminal tail of mGluR1a in an agonist-dependent manner and plays a role in regulating of mGluR1a signaling and intracellular trafficking in human embryonic kidney 293 cells. Specifically, Rab8 expression attenuates mGluR1a-mediated inositol phosphate formation and calcium release from mouse neurons in a PKC-dependent manner, while increasing cell surface mGluR1a expression via decreased receptor endocytosis. These experiments provide us with an understanding of the role Rabs play in coordinated regulation of mGluR1a and how this impacts mGluR1a signaling.
authors.affiliation: J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, University of Western Ontario, London, Ontario N6A 5K8, Canada.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Esseltine
authors.forename: Fabiola M
authors.initials: FM
authors.lastname: Ribeiro
authors.forename: Stephen S G
authors.initials: SS
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D019921:Biotinylation; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009474:Neurons / Q000502:physiology; D011247:Pregnancy; D011493:Protein Kinase C / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000502:physiology*
chemical_list: D007295:Inositol Phosphates; D011956:Receptors, Cell Surface; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins