Health Sciences Library & Informatics Center
1 University of New Mexico
Albuquerque, NM 87131-0001
Deapartment of Neurology
Building: NRF; Room No: 1320
Albuquerque NM 87131
Doctor of Philosophy : Jadavpur University , (1995)
Research in my laboratory focuses on understanding the cellular mechanisms of neuronal injury and development of strategies for intervention in neurological disorders related to excitotoxicity and oxidative stress. Excitotoxicity refers to the deleterious effects of overstimulation of the neurotransmitter glutamate. Excessive neuronal Ca2+ entry and activation of series of Ca2+ dependent enzymes along with enhanced oxidative stress induce excitotoxic neuronal cell death. Excitotoxicity is known to be involved in several neurological diseases, including focal cerebral ischemia, traumatic brain injury, Huntington’s chorea and amyotrophic lateral sclerosis. To evaluate the role of the brain-specific tyrosine phosphatase STEP (STriatal Enriched Phosphatase) in neurological disorders related to excitotoxicity we use a broad range of interdisciplinary approaches, including neuronal cultures, rodent models of cerebral ischemia, mouse genetic models, biochemical, molecular, immunohistochemical, behavioral and magnetic resonance imaging strategies. Our earlier work showed that the activity and stability of STEP is tightly regulated by several post-translational modifications that include phosphorylation, polyubiquitination and intermolecular dimerization. The neurotransmitters dopamine and glutamate play critical roles in regulating the activity of STEP. Additional studies using cell culture models of excitotoxicity and hypoxia-reoxygenation injury as well as an animal model of focal cerebral ischemia demonstrated a role of STEP in neuroprotection through down regulation of p38 mitogen activated protein kinase, a stress-activated kinase that is involved in neuroinflammation and death. Our current focus is to elucidate additional signaling pathways that regulate the activity of STEP and identify novel target molecules that are modulated by STEP signaling. We are also evaluating whether a STEP-derived peptide could reduce the consequences of ischemic injury and impart long-term neuroprotection. The STEP KO mice are also being used to evaluate the molecular basis of exacerbated ischemic brain injury in the absence of STEP. Another interest of the laboratory is to evaluate the role of STEP in regulating the key pathways affected by oxidative stress during aging and age-associated increase in hypertension.
* Mukherjee S, Poddar R, Deb I, Paul S (2011) Dephosphorylation of specific sites in the KIS domain leads to ubiquitin-mediated degradation of the tyrosine phosphatase STEP. Biochem J. 15:115-125.
* Deb I, Poddar R, Paul S (2011) Oxidative stress induced dimerization inhibits the activity of the non-receptor tyrosine phosphatase STEP61. J. Neurochem. 116: 1097-1011.
* Paul S, Connor JA. (2010) NR2B-NMDA receptor mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP and ERK MAP kinase signaling. J. Neurochem. 114: 1107-1118.
* Poddar R, Deb I, Paul S (2010) NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced cell death. J. Neurochem. 115: 1350-1362.
* Venkitaramani D*, Paul S*, Ding L, Tressler L, Allen M, Sacca R, Picciotto MR, Lombroso PJ (2009) Knockout of STriatal-Enriched protein tyrosine Phosphatase (STEP) in mice results in increased ERK1/2 activity. Synapse. 63:69-81.
* Paul S, Olausson P, Venkitaramani DV, Ruchkina I, Moran TD, Tronson N, Mills E, Hakim S, Salter MW, Taylor JR, Lombroso PJ (2007) The protein tyrosine phosphatase STEP gates long-term potentiation and fear memory in the lateral amygdala. Biol. Pyschiatry. 61:1049-1061.
* Snyder EM, Nong Y, Almedia CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P, (2005) Regulation of NMDA receptor trafficking by amyloid-b. Nature Neurosci. 6:34-42.
* Valjent E, Pascoli V, Svenningson P, Paul S, Enslen H, Corvol J-C, Stipanovich A, Caboche J, Lombroso PJ, Nairn AC, Greengard P, Hervé D, Girault J-A (2005) Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc. Natl. Acad. Sci. (USA) 102:253-264.
* Paul S, Nairn AC, Wang P, Lombroso PJ (2003) Glutamate/NMDA receptor mediated activation of a protein tyrosine phosphatase, STEP, leads to the release of ERK2 through tyrosine de-phosphorylation. Nature Neurosci. 6:34-42.
* Paul S, Snyder GL, Yokakura H, Picciotto MR, Nairn AC, Lombroso PJ (2000) Dopamine/D1 receptor mediates the phosphorylation and inactivation of the protein tyrosine phosphatase, STEP, through a PKA-dependent pathway. J. Neurosci. 20:5630-5638.