title: Transduction of group I mGluR-mediated synaptic plasticity by β-arrestin2 signalling.
abstract: Conventional signalling by the group I metabotropic glutamate receptors, mGluR1 and mGluR5, occurs through G-protein coupling, but evidence suggests they might also utilize other, non-canonical effector pathways. Here we test whether group I mGluRs require β-arrestin signalling during specific forms of plasticity at hippocampal excitatory synapses. We find that genetic ablation of β-arrestin2, but not β-arrestin1, results in deficits in plasticity mediated by mGlu1 receptors in CA3 pyramidal neurons and by mGlu5 receptors in CA1 pyramidal neurons. Pharmacological studies additionally support roles for Src kinases and MAPK/ERK downstream of β-arrestin2 in CA3 neurons. mGluR1 modulation of intrinsic conductances is otherwise preserved in β-arrestin2-/-mice with the exception of a rebound depolarization, and non-mGluR-mediated long-term potentiation is unaltered. These results reveal a signalling pathway engaged by group I mGluRs to effect changes in synaptic and cell intrinsic physiology dependent upon β-arrestin rather than G proteins. Pharmacological manipulation of mGluRs with effector-biased ligands could lead to novel therapies to treat neurological disease.
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Eng
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kelver
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Tristan P
authors.initials: TP
authors.lastname: Hedrick
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Swanson
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009473:Neuronal Plasticity; D017966:Pyramidal Cells / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013569:Synapses / Q000502:physiology; D000071559:beta-Arrestin 1 / Q000235:genetics / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; C104077:metabotropic glutamate receptor type 1