Assistant Professor, Dominick P. Purpura Department of Neuroscience
Molecular mechanisms of metabotropic glutamate receptor function.
Abnormal maturation of brain circuitry during development is a critical determinant of pathological manifestations in many neuropsychiatric conditions including intellectual disability, Fragile X syndrome, and schizophrenia. A growing body of evidence from studies in human subjects and animal models has established a link between dysfunctions in glutamatergic neurotransmission and developmental brain abnormalities associated with these conditions. Group I metabotropic glutamate receptors, mGlu1 and mGlu5, are G protein-coupled receptors critical to the formation and maintenance of brain circuitry and activity-dependent synaptic plasticity, a cellular substrate of learning and memory. Dysregulation of group I mGlu receptor activity is implicated in neurodevelopmental disorders including Fragile X syndrome and schizophrenia.
Research in the laboratory focuses on elucidating the molecular and cellular underpinnings of metabotropic glutamatergic neurotransmission in the brain, with the ultimate goal of developing a molecular rationale for targeted interventions in neuropsychiatric disorders. We use a combination of molecular biology, biochemistry and imaging techniques to uncover the molecular mechanisms underlying temporo-spatial regulation of mGluR signaling and to examine mGluR functions in neuronal homeostasis and synaptic transmission. Ongoing studies pursue interrelated lines of investigation by examining the role of adaptor proteins in orchestrating and fine-tuning mGluR activity under physiological conditions and in animal models of Fragile X syndrome; and by investigating the mechanisms by which mGluR signaling contributes to synaptogenesis and neuronal maturation.
Francesconi, A., Kalinowska, M., Castillo, C. (2014) Quantitative profiling of brain lipid raft proteome in a mouse model of autism. PLoS One (under review).
Kumari, R., Castillo, C., and Francesconi, A. (2013) Agonist-dependent signaling by group I metabotropic glutamate receptors is regulated by association with lipid domains J. Biol. Chem. 288, 32004-32019. PMCID: PMC3814796
Kumari, R., and A. Francesconi. (2011). Identification of GPCR localization in Detergent-Resistant Membranes. Methods Mol. Biol. 746:411-423.
Takayasu, Y., Takeuchi, K., Kumari, R., Bennett, M.V., Zukin, R.S., and A. Francesconi. (2010) Caveolin-1 knockout mice exhibit impaired induction of mGluR-dependent long-term depression at CA3-CA1 synapses. Proc. Natl. Acad. Sci. U S A. 107:21778-83.
Francesconi, A., Kumari, R. and R.S. Zukin. (2009). Proteomic analysis reveals novel binding partners of metabotropic glutamatereceptor 1. J. Neurochem. 108:1515-1525.
Francesconi, A., Kumari, R. and R.S. Zukin. (2009). Regulation of group I mGluR trafficking and signaling by the caveolar/lipid raft pathway. J. Neurosci. 29:3590-3602.
Francesconi, A., and Duvoisin, R.M. (2004). Divalent cations modulate the activity of metabotropic glutamate receptors. J. Neurosci. Res. 75, 472-479.
Francesconi, A., and Duvoisin, R. M. (2002). Alternative splicing unmasks dendritic and axonal targeting signals in mGluR1. J. Neurosci. 22, 2196-2205.
Francesconi, A., and Duvoisin, R.M. (2000). Opposing effects of PKC and PKA on metabotropic glutamate receptor signaling. Selective desensitization of the InsP/Ca2+ pathway by phosphorylation of the receptor-G protein coupling domain. Proc. Natl. Acad. Sci. USA 97, 6185-6190.
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Albert Einstein College of Medicine
Rose F. Kennedy Center
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Bronx, NY 10461