Beta-arrestins are cytosolic proteins that interact with the carboxy-terminal tails of seven-transmembrane receptors (i.e., GPCRs) and play a role in desensitization, internalization, and scaffolding other proteins that initiate intracellular signalng cascades independent of G protein activation. Because the latter non-canonical signaling mode is a relatively new discovery, the extent to which beta-arrestins transduce G protein-independent signaling downstream of most types of GPCRs is unknown. Metabotropic glutamate receptors (mGluRs) represent one such family of receptors with a largely uncharacterized relationship to beta-arrestins. In this project, we will test the hypothesis that group I mGluRs (mGluR1 and mGluR5) have the potential to activate b-arrestin-dependent signaling pathways, and that signaling through non-G protein-mediated mechanisms in part underlie mGluR-dependent forms of synaptic plasticity in the hippocampus.
In Specific Aim 1, we will determine which group I mGluRs associate with b-arrestin-1 and -2 in the mammalian brain and examine how an mGluR1-dependent form of hippocampal plasticity at mossy fiber - CA3 pyramidal neuron synapses is altered by association with one or both b-arrestins.
In Specific Aim 2, we will elucidate which signaling cascades underlie mGluR1-dependent plasticity at mossy fiber synapses.
In Specific Aim 3, we will test the role of b-arrestins in a group I mGluR-dependent plasticity at Schaffer collateral - CA1 pyramidal neuron synapses. These experiments have the potential to reveal an unexpected contribution by novel signaling pathways, those downstream of mGluRs but independent of canonical G protein processes, in synaptic plasticity in the hippocampus. The existence of beta-arrestin-dependent signaling would also support the potential development of biased ligands for mGluRs. The outcomes of this study could therefore yield insight into new strategies for therapeutic targeting of group I mGluRs, which in recent years has been pursued for a number of neuropathologies.

Public Health Relevance

Understanding how G-protein coupled receptors (GPCRs) signal is a fundamental goal in neuroscience, because these receptors comprise the largest group of drug targets in the central nervous system. New research suggest that G protein-independent signaling mechanisms initiated by b-arrestin proteins play a significant but poorly understood role in GPCR signaling processes. We will test the role of b-arrestins in neurophysiological actions mediated by metabotropic glutamate receptors, a family of GPCRs of critical importance to excitatory synaptic transmission and plasticity in the CNS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Stewart, Randall R
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Northwestern University at Chicago
Schools of Medicine
United States
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Eng, Andrew G; Kelver, Daniel A; Hedrick, Tristan P et al. (2016) Transduction of group I mGluR-mediated synaptic plasticity by ?-arrestin2 signalling. Nat Commun 7:13571