title: Glutamate receptor δ2 associates with metabotropic glutamate receptor 1 (mGluR1), protein kinase Cγ, and canonical transient receptor potential 3 and regulates mGluR1-mediated synaptic transmission in cerebellar Purkinje neurons.
abstract: Cerebellar motor coordination and cerebellar Purkinje cell synaptic function require metabotropic glutamate receptor 1 (mGluR1, Grm1). We used an unbiased proteomic approach to identify protein partners for mGluR1 in cerebellum and discovered glutamate receptor δ2 (GluRδ2, Grid2, GluΔ2) and protein kinase Cγ (PKCγ) as major interactors. We also found canonical transient receptor potential 3 (TRPC3), which is also needed for mGluR1-dependent slow EPSCs and motor coordination and associates with mGluR1, GluRδ2, and PKCγ. Mutation of GluRδ2 changes subcellular fractionation of mGluR1 and TRPC3 to increase their surface expression. Fitting with this, mGluR1-evoked inward currents are increased in GluRδ2 mutant mice. Moreover, loss of GluRδ2 disrupts the time course of mGluR1-dependent synaptic transmission at parallel fiber-Purkinje cells synapses. Thus, GluRδ2 is part of the mGluR1 signaling complex needed for cerebellar synaptic function and motor coordination, explaining the shared cerebellar motor phenotype that manifests in mutants of the mGluR1 and GluRδ2 signaling pathways.
authors.affiliation: Lilly Research Laboratory, Indianapolis, Indiana 46285, USA. katoak@lilly.com
authors.forename: Akihiko S
authors.initials: AS
authors.lastname: Kato
authors.forename: Michael D
authors.initials: MD
authors.lastname: Knierman
authors.forename: Edward R
authors.initials: ER
authors.lastname: Siuda
authors.forename: John T R
authors.initials: JT
authors.lastname: Isaac
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
authors.forename: David S
authors.initials: DS
authors.lastname: Bredt
mesh_terms: D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011493:Protein Kinase C / Q000502:physiology*; D011689:Purkinje Cells / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology; D017470:Receptors, Glutamate / Q000235:genetics / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012995:Solubility; D013347:Subcellular Fractions / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D050052:TRPC Cation Channels / Q000502:physiology*
chemical_list: D011956:Receptors, Cell Surface; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C107913:glutamate receptor delta 2; C104077:metabotropic glutamate receptor type 1; C087857:protein kinase C gamma; D011493:Protein Kinase C