The neurotransmitter glutamate activates in the central nervous system several subtypes of excitatory amino acid receptors that play a key role in the phenomena of learning and memory. These receptors are likewise implicated in a variety of neurodegenerative diseases. My research goal is to understand the molecular mechanisms of intracellular signal transduction associated with the particular subtypes of excitatory amino acid receptors, and to establish their functional significance.

One project uses the techniques of fluorescent imaging to study the role of ionotropic glutamate receptors in controlling the intracellular concentrations of calcium and sodium ions, and their significance in the mechanisms of glutamate-induced neurotoxicity and in the generation of different cascades of second messengers.

A second project focuses on the study of G protein-coupled metabotropic glutamate receptors. They are coupled either to the activation of the hydrolysis of membrane inositol phospholipids or to the inhibition of adenylate cyclase, but their physiological significance remains obscure. Using primary cultures of neuronal and glial cells, this project aims to identify the functional differences between metabotropic glutamate receptors, their pharmacological profiles, and the developmental patterns of receptor expression.

Since the neurotransmitter glutamate activates all subtypes of glutamate receptors, the logistics of its action involve interactions between these receptors at the level of their ionotropic and metabotropic signal transduction mechanisms. Indeed, the studies of these interactions may be especially fruitful if performed at the single cell level. Therefore, one of the major goals of my laboratory, projecting into future research, is the development of fluorescent imaging techniques allowing such measurements.

Selected Publications:

• Pshenichkin S, Dolińska M, Klauzińska M, Luchenko V, Grajkowska E, Wroblewski JT.: Dual neurotoxic and neuroprotective role of metabotropic glutamate receptor 1 in conditions of trophic deprivation - possible role as a dependence receptor. Neuropharmacology. 55:500-8, Sep 2008

• Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT.: Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists. Neuropharmacology. 52:744-54, 2007

• Iso Y, Grajkowska E, Wroblewski JT, Davis J, Goeders NE, Johnson KM, Sanker S, Roth BL, Tueckmantel W, Kozikowski AP.: Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications. J Med Chem. 49:1080-100, 2006

• Makarewicz D, Gadamski R, Ziembowicz A, Kozikowski AP, Wroblewski JT, Lazarewicz JW.: Neuroprotective effects of the agonist of metabotropic glutamate receptors ABHxD-I in two animal models of cerebral ischaemia. Resuscitation. 68:119-26, 2006

• Alagille D, Baldwin RM, Roth BL, Wroblewski JT, Grajkowska E, Tamagnan GD.: Functionalization at position 3 of the phenyl ring of the potent mGluR5 noncompetitive antagonists MPEP. Bioorg Med Chem Lett.  15:945-949, 2005

• Alagille D, Baldwin RM, Roth BL, Wroblewski JT, Grajkowska E, Tamagnan GD.: Synthesis and receptor assay of aromatic-ethynyl-aromatic derivatives with potent mGluR5 antagonist activity. Bioorg Med Chem. 13:197-209, 2005

• Olszewski RT, Bukhari N, Zhou J, Kozikowski AP, Wroblewski JT, Shamimi-Noori S, Wroblewska B, Bzdega T, Vicini S, Barton FB, Neale JH.: NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem. 89:876-885, 2004

• Kozikowski AP, Zhang J, Nan F, Petukhov PA, Grajkowska E, Wroblewski JT, Yamamoto T, Bzdega T, Wroblewska B, Neale JH.: Synthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II: efficacy as analgesic agents. J Med Chem.  47:1729-38, 2004

• Shi Q, Hufeisen SJ, Wroblewski JT, Nadeau JH, Roth BL.: L-homocysteine sulfinic acid and L-homocysteic acid stimulate phosphoinositide hydrolysis in rat cortical neurons. J Pharmacol Exp Ther. 305:131-42, 2003

• Rong SB, Zhang J, Neale JH, Wroblewski JT, Wang S, Kozikowski AP.: Molecular modeling of the interactions of glutamate carboxypeptidase II with its potent NAAG-based inhibitors. J Med Chem. 12;45:4140-4152, 2002

• Mukhopadhyaya JK, Kozikowski AP, Grajkowska E, Pshenichkin S, Wroblewski JT.: Synthesis of N(1)-substituted analogues of (2R,4R)-4-amino-pyrrolidine-2,4-dicarboxylic acid as agonists, partial agonists, and antagonists of group II metabotropic glutamate receptors. Bioorg Med Chem Lett. 11:1919-1924, 2001

• Kozikowski AP, Nan F, Conti P, Zhang J, Ramadan E, Bzdega T, Wroblewska B, Neale JH, Pshenichkin S, Wroblewski JT.: Design of remarkably simple, yet potent urea-based inhibitors of glutamate carboxypeptidase II (NAALADase). J Med Chem. 44:298-301, 2001

• Nan F, Bzdega T, Pshenichkin S, Wroblewski JT, Wroblewska B, Neale JH, Kozikowski AP.: Dual function glutamate-related ligands: discovery of a novel, potent inhibitor of glutamate carboxypeptidase II possessing mGluR3 agonist activity. J Med Chem. 43:772-774, 2000

• Kozikowski AP, Araldi GL, Tückmantel W, Pshenichkin S, Surina E, Wroblewski JT.: 1-amino-APDC, a partial agonist of group II metabotropic glutamate receptors with neuroprotective properties. Bioorg Med Chem Lett. 9:1721-1726, 1999

• Ma D, Ma Z, Kozikowski AP, Pshenichkin S, Wroblewski JT.: Synthesis and biological evaluation of two analogues of (S)-alpha-methyl-3-carboxyphenylalanine. Bioorg Med Chem Lett. 8:2447-50, 1998

• Bruno V, Wroblewska B, Wroblewski JT, Fiore L, Nicoletti F.: Neuroprotective activity of N-acetylaspartylglutamate in cultured cortical cells. Neurosci. 85:751-757 ,1998

• Kozikowski AP, Steensma D, Araldi GL, Tückmantel W, Wang S, Pshenichkin S, Surina E, Wroblewski JT.: Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I, a potent mGluR agonist. J Med Chem. 41:1641-1650, 1998