Inhibition of metabotropic glutamate receptor signaling by the huntingtin-binding protein optineurin.
Huntington disease is caused by a polyglutamine expansion in the huntingtin protein (Htt) and is associated with excitotoxic death of striatal neurons. Group I metabotropic glutamate receptors (mGluRs) that are coupled to inositol 1,4,5-triphosphate formation and the release of intracellular Ca(2+) stores play an important role in regulating neuronal function. We show here that mGluRs interact with the Htt-binding protein optineurin that is also linked to normal pressure open angled glaucoma and, when expressed in HEK 293 cells, optineurin functions to antagonize agonist-stimulated mGluR1a signaling. We find that Htt is co-precipitated with mGluR1a and that mutant Htt functions to facilitate optineurin-mediated attenuation of mGluR1a signaling. In striatal cell lines derived from Htt(Q111/Q111) mutant knock-in mice mGluR5-stimulated inositol phosphate formation is also severely impaired when compared with striatal cells derived from Htt(Q7/Q7) knock-in mice. In addition, we show that a missense single nucleotide polymorphism optineurin H486R variant previously identified to be associated with glaucoma is selectively impaired in mutant Htt binding. Although optineurin H486R retains the capacity to bind to mGluR1a, optineurin H486R-dependent attenuation of mGluR1a signaling is not enhanced by the expression of mutant Htt. Because G protein-coupled receptor kinase 2 (GRK2) protein expression is relatively low in striatal tissue, we propose that optineurin may substitute for GRK2 in the striatum to mediate mGluR desensitization. Taken together, these studies identify a novel mechanism for mGluR desensitization and an additional biochemical link between altered glutamate receptor signaling and Huntington disease.
Anborgh
Pieter H
PH
Cell Biology Research Group, Robarts Research Institute and Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario N6A 5K8, Canada.
Godin
Christina
C
Pampillo
Macarena
M
Dhami
Gurpreet K
GK
Dale
Lianne B
LB
Cregan
Sean P
SP
Truant
Ray
R
Ferguson
Stephen S G
SS
D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054769:G-Protein-Coupled Receptor Kinase 2; D015723:Gene Library; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D006801:Humans; D000071058:Huntingtin Protein; D015151:Immunoblotting; D047468:Immunoprecipitation; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007295:Inositol Phosphates / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D035582:Transcription Factor TFIIIA / Q000737:chemistry*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism
D018797:Cell Cycle Proteins; D018076:DNA, Complementary; C086055:HTT protein, human; D000071058:Huntingtin Protein; D007295:Inositol Phosphates; D008055:Lipids; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C409460:OPTN protein, human; D018094:Receptors, Metabotropic Glutamate; D013778:Tetrazolium Salts; D013844:Thiazoles; D035582:Transcription Factor TFIIIA; D049452:Green Fluorescent Proteins; D006639:Histidine; D015544:Inositol 1,4,5-Trisphosphate; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; C022616:thiazolyl blue; D002118:Calcium