mGluRs are G protein-coupled receptors enriched at excitatory synapses throughout the brain where they act both pre- and postsynaptically to regulate glutamatergic neurotransmission. Signaling by mGluRs is critical to synaptic circuitry formation during development and is implicated in forms of activity-dependent synaptic plasticity. Dysregulation of mGluR signaling is implicated in many neurological and psychiatric disorders linked to abnormal development, including Fragile X syndrome, the most common inherited form of mental retardation, epilepsy, schizophrenia, and addiction. The overall objective of this proposal is to understand the molecular mechanisms underlying the regulation of mGluR signaling by association with a key scaffolding protein in the brain. Preliminary evidence indicates that postsynaptic group I mGluRs (mGluR1/5) bind caveolin-1 and associate with membrane rafts. Caveolin-1, the main structural component of caveolae, acts as a molecular scaffold for a large number of signaling effector proteins and membrane receptors. Lipid rafts and caveolae are specialized membrane microdomains that serve as platforms to compartmentalize signaling activities at the cell surface. The hypothesis underlying the proposed studies is that association with caveolin-1 and membrane rafts regulates mGluR-dependent signal transduction. This proposal builds on our initial observations by pursuing the following Specific Aims: 1) Assess the role of caveolin-1 in the regulation of mGluR1/5-dependent changes in synapse composition. Experiments will examine the impact of caveolin-1 on 1) mGluR1/5-induced internalization of AMPA receptors;2) mGluR1/5-induced local synthesis of proteins critical for synaptic plasticity;and 3) mGluR1/5-induced activation of transcription factors involved in memory storage. 2) Determine whether association with membrane rafts and caveolin-1 regulates mGluR signaling to effector proteins. Experiments will examine the association of mGluRs with signaling proteins in rafts vs non-raft membrane domains and the role of caveolin-1 in regulating mGluR signaling to the PLC/InsP3/Ca2+ and ERK-MAPK pathways. Collectively, these studies will provide important insights not only into the regulation of mGluR signaling but also into mechanisms relevant to the establishment and maintenance of neuronal circuitry under physiological and pathological conditions, including inherited forms of mental retardation such as Fragile X syndrome.

Public Health Relevance

mGluRs are G protein-coupled receptors enriched at excitatory synapses throughout the brain where they act both pre- and postsynaptically to regulate glutamatergic neurotransmission;signaling by mGluRs is critical to synaptic circuitry formation during development and is implicated in forms of activity-dependent synaptic plasticity. The overall objective of this proposal is to understand the molecular mechanisms underlying the regulation of mGluR signaling by association with a key scaffolding protein in the brain;these studies will provide insights into mechanisms relevant to the establishment and maintenance of neuronal circuitry under physiological and pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH082870-04
Application #
8247167
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Asanuma, Chiiko
Project Start
2009-06-15
Project End
2013-12-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$410,850
Indirect Cost
$163,350
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Kumari, Ranju; Castillo, Catherine; Francesconi, Anna (2013) Agonist-dependent signaling by group I metabotropic glutamate receptors is regulated by association with lipid domains. J Biol Chem 288:32004-19
Kumari, Ranju; Francesconi, Anna (2011) Identification of GPCR localization in detergent resistant membranes. Methods Mol Biol 746:411-23