Discovering

INDIVIDUAL RESEARCHER

Alexander A. Mongin , Ph.D.
Assistant Professor
e-mail: MonginA@mail.AMC.edu

Education

1995 - Ph.D. from National Academy of Sciences of Belarus

Current Research

My research interests are focused on the cellular and molecular mechanisms contributing to brain damage and neurological deficits in stroke and ischemia. The ongoing work in this laboratory explores pathological mechanisms of neural tissue damage along two lines. In one area of our research we investigate the link between pathological swelling of glial cells and release of excitatory amino acids (glutamate and aspartate). Both of these processes have been connected to the extensive tissue damage in stroke and a number of other neurological disorders. However, the exact relationship between cell swelling and pathological glutamate release remains unclear. According to our working hypothesis, swelling of glial cells causes activation of volume-regulated anion channels (VRACs), which are permeable towards chloride and amino acids. The normal role of these channels is to maintain cell volume at a constant level during cell proliferation, throughout the periods of extensive uptake of osmotically active molecules, or during abrupt changes in the concentration of extracellular ions. However, in pathology VRACs are thought to mediate a substantial fraction of glutamate release from swollen cells (predominantly astrocytes) and thus contribute to glutamate-mediated neuronal damage. Our work is aimed at establishing the molecular nature of VRACs, exploring the mechanisms of their regulation, and elucidating their contribution to brain damage in ischemia and other pathological states. To address these questions we quantify VRAC-mediated excitatory amino acid fluxes by measuring isotope-labeled D-aspartate efflux in cultured cells, and using microdialysis approach in vivo. We further use a combination of electrophysiology and molecular biological approaches to explore the mechanisms of VRAC activation in astrocytes and heterologous expression systems. The second part of our studies is devoted to the role of nitric oxide and related reactive nitrogen species (RNS) in stroke pathology. We identify protein molecules, which are oxidized, nitrated and/or nitrosylated by RNS and evaluate the role for such RNS-related modifications in the long-term impairment of synaptic transmission in postischemic brain. Our main working model here is that nitric oxide, while produced at the pathological levels, potently down-regulates neurotransmitter release in the ischemic brain via chemical modification of presynaptic proteins responsible for docking and fusion of the synaptic vesicles. We use synaptosomal preparation to evaluate the effects of nitric oxide on the presynaptic neurotransmitter release, and utilize protein samples prepared from ischemic animal brain to monitor for protein modifications in vivo.

References

1. Abdullaev, I.F., Rudkouskaya, A., Schools, G.P., Kimelberg, H.K., and Mongin, A.A. (2006) Comparison of pharmacological profiles of volume-dependent chloride currents and organic osmolyte release in primary cultured astrocytes. J. Physiol. (London) 572 677-689.



2. Haskew-Layton, R.E., Mongin, A.A., and Kimelberg, H.K. (2005) Hydrogen peroxide potentiates volume-sensitive excitatory amino acid release via a mechanism involving Ca2+/calmodulin-dependent protein kinase II. J. Biol Chem. 280, 3548-3554.



3. Mongin, A.A. and Kimelberg, H.K. (2005) ATP stimulates anion channel-mediated organic osmolyte release from cultured rat astrocytes via multiple Ca2+-sensitive mechanisms. Am. J. Physiol. Cell Physiol. 288, C204-C213.



4. Mongin, A.A., and Kimelberg, H.K. (2005) Astrocytic swelling in neuropathology. In: Neuroglia (H. Kettenmann and B. R. Ransom, eds.), 2nd edition. New York, Oxford: Oxford University Press. Pp.550-562.



5. Mongin, A. A. (2002) Nitric oxide may contribute to the long-term impairment of synaptic transmission after transient ischemia. Stroke 33, 2348-2350.