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 signaling cascades independent of G protein activation. Because the latter non-canonical signaling mode is a relatively new discovery, the extent to which β-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 β-arrestins. In this project, we will test the hypothesis that group I mGluRs (mGluR1 and mGluR5) have the potential to activate β-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 β-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 β-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 β-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 β-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.
|Effective start/end date||7/1/14 → 6/30/16|
- National Institute of Neurological Disorders and Stroke (5R21NS088916-02)