GPR179 is required for high sensitivity of the mGluR6 signaling cascade in depolarizing bipolar cells.
Parallel visual pathways are initiated at the first retinal synapse by signaling between the rod and cone photoreceptors and two general classes of bipolar cells. For normal function, ON or depolarizing bipolar cells (DBCs) require the G-protein-coupled receptor, mGluR6, an intact G-protein-coupled cascade and the transient receptor potential melastatin 1 (TRPM1) cation channel. In addition, another seven transmembrane protein, GPR179, is required for DBC function and recruits the regulators of G-protein signaling (RGS) proteins, RGS7 and RGS11, to the dendritic tips of the DBCs. Here we use the Gpr179(nob5) mouse, which lacks GPR179 and has a no b-wave electroretinogram (ERG) phenotype, to demonstrate that despite the absence of both GPR179 and RGS7/RGS11, a small dark-adapted ERG b-wave remains and can be enhanced with long duration flashes. Consistent with the ERG, the mGluR6-mediated gating of TRPM1 can be evoked pharmacologically in Gpr179(nob5) and RGS7(-/-)/RGS11(-/-) rod BCs if strong stimulation conditions are used. In contrast, direct gating of TRPM1 by capsaicin in RGS7(-/-)/RGS11(-/-) and WT rod BCs is similar, but severely compromised in Gpr179(nob5) rod BCs. Noise and standing current analyses indicate that the remaining channels in Gpr179(nob5) and RGS7(-/-)/RGS11(-/-) rod BCs have a very low open probability. We propose that GPR179 along with RGS7 and RGS11 controls the ability of the mGluR6 cascade to gate TRPM1. In addition to its role in localizing RGS7 and RGS11 to the dendritic tips, GPR179 via a direct interaction with the TRPM1 channel alters its ability to be gated directly by capsaicin.
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky 40202, Department of Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky 40292, Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky 40202, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio 44106, Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195, Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, and Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky 40202.
Thomas A
TA
Ray
Kathryn M
KM
Heath
Nazarul
N
Hasan
Jennifer M
JM
Noel
Ivy S
IS
Samuels
Kirill A
KA
Martemyanov
Neal S
NS
Peachey
Maureen A
MA
McCall
Ronald G
RG
Gregg
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002461:Cell Line, Transformed; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011509:Proteoglycans / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000378:metabolism; D051245:Retinal Bipolar Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013331:Strychnine / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; C575060:GPR179 protein, mouse; C547869:Gabrr1 protein, mouse; D018684:Glycine Agents; C527362:Nyx protein, rat; D011509:Proteoglycans; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D050053:TRPM Cation Channels; C116297:Trpm1 protein, mouse; C104331:cyclopropyl-4-phosphonophenylglycine; C113897:metabotropic glutamate receptor 6; D013331:Strychnine; D002211:Capsaicin; D005998:Glycine
GPR179; TRPM1; mGluR6; night blindness; retina; rod bipolar