title: Intermolecular Interaction between Anchoring Subunits Specify Subcellular Targeting and Function of RGS Proteins in Retina ON-Bipolar Neurons.
abstract: In vertebrate retina, light responses generated by the rod photoreceptors are transmitted to the second-order neurons, the ON-bipolar cells (ON-BC), and this communication is indispensible for vision in dim light. In ON-BCs, synaptic transmission is initiated by the metabotropic glutamate receptor, mGluR6, that signals via the G-protein Go to control opening of the effector ion channel, TRPM1. A key role in this process belongs to the GTPase Activating Protein (GAP) complex that catalyzes Go inactivation upon light-induced suppression of glutamate release in rod photoreceptors, thereby driving ON-BC depolarization to changes in synaptic input. The GAP complex has a striking molecular complexity. It contains two Regulator of G-protein Signaling (RGS) proteins RGS7 and RGS11 that directly act on Go and two adaptor subunits: RGS Anchor Protein (R9AP) and the orphan receptor, GPR179. Here we examined the organizational principles of the GAP complex in ON-BCs. Biochemical experiments revealed that RGS7 binds to a conserved site in GPR179 and that RGS11 in vivo forms a complex only with R9AP. R9AP and GPR179 are further integrated via direct protein-protein interactions involving their cytoplasmic domains. Elimination of GPR179 prevents postsynaptic accumulation of R9AP. Furthermore, concurrent knock-out of both R9AP and RGS7 does not reconfigure the GAP complex and completely abolishes synaptic transmission, resulting in a novel mouse model of night blindness. Based on these results, we propose a model of hierarchical assembly and function of the GAP complex that supports ON-BCs visual signaling.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, and.
authors.forename: Ignacio
authors.identifier: http://orcid.org/0000-0003-0099-3535
authors.initials: I
authors.lastname: Sarria
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, and.
authors.forename: Cesare
authors.initials: C
authors.lastname: Orlandi
authors.affiliation: Departments of Ophthalmology and Visual Sciences, Anatomical Sciences and Neurobiology, and.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McCall
authors.affiliation: Anatomical Sciences and Neurobiology, and Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky 40292.
authors.forename: Ronald G
authors.identifier: http://orcid.org/0000-0001-5805-224X
authors.initials: RG
authors.lastname: Gregg
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, and kirill@scripps.edu.
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
mesh_terms: D000429:Alcohol Oxidoreductases; D000818:Animals; D019256:Cadmium Chloride / Q000494:pharmacology; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008027:Light; D046911:Macromolecular Substances / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D010750:Phosphoproteins / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D051245:Retinal Bipolar Cells / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C121670:GPR17 protein, human; D046911:Macromolecular Substances; D008565:Membrane Proteins; D010750:Phosphoproteins; C508769:R9AP protein, mouse; D020710:RGS Proteins; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; C492038:Rgs7 protein, mouse; C113897:metabotropic glutamate receptor 6; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; D019256:Cadmium Chloride
keywords: G-protein signaling; RGS proteins; retina; synaptic transmission; vision