Intermolecular Interaction between Anchoring Subunits Specify Subcellular Targeting and Function of RGS Proteins in Retina ON-Bipolar Neurons

J Neurosci. 2016 Mar 9;36(10):2915-25. doi: 10.1523/JNEUROSCI.3833-15.2016.


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.

Keywords: G-protein signaling; RGS proteins; retina; synaptic transmission; vision.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol Oxidoreductases
  • Animals
  • Cadmium Chloride / pharmacology
  • Co-Repressor Proteins
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • HEK293 Cells
  • Humans
  • Light
  • Macromolecular Substances / metabolism
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Phosphoproteins / metabolism
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Metabotropic Glutamate / metabolism
  • Retina / cytology*
  • Retinal Bipolar Cells / physiology*
  • Synaptic Transmission / physiology


  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • GPR17 protein, human
  • Macromolecular Substances
  • Membrane Proteins
  • Phosphoproteins
  • R9AP protein, mouse
  • RGS Proteins
  • Receptors, G-Protein-Coupled
  • Receptors, Metabotropic Glutamate
  • Rgs7 protein, mouse
  • metabotropic glutamate receptor 6
  • Alcohol Oxidoreductases
  • Ctbp2 protein, mouse
  • Cadmium Chloride