Glutamate is the primary excitatory neurotransmitter utilized by neurons in the central nervous system. Despite the prominence of glutamate as a vehicle for normal CNS function, it is also a potent neurotoxin when synaptic levels remain elevated above normal resting concentrations (approximately 1 muM) even for a short interval. Neural toxicity can occur due to release of transmitter glutamate that exceeds the capacity of the usual mechanisms for clearance of glutamate from the synapse, and/or when function of the clearance mechanisms themselves become compromised. Our preliminary work shows that localized biochemical signals modify glutamate reuptake by rat brain astrocytes in ways that can either compromise or enhance the clearance process. Astrocytes are known to play a prominent role in the clearance of synaptic glutamate. This proposal focuses on the role that astrocyte glutamate transport systems play in maintaining extracellular glutamate concentrations at levels which allow appropriate ongoing function of neural transmission events. Primary aims are to define the biochemical regulatory mechanisms which modulate active and passive astrocytic glutamate transport systems that determine steady state intra- and extra-cellular CNS glutamate levels. The renewal builds on recent preliminary work in which we have shown that astrocytic glutamate clearance from the synapse by the GLAST cotransport protein can be markedly stimulated by various 'signal molecules' which implicate the importance of cellular events involving protein kinase C, protein tyrosine kinase, phosphoprotein phosphatases, and 'targeting' of transport protein to the plasma membrane.
Specific aims are described which focus on providing detail for the role each of these processes plays in regulating astrocytic glutamate transporter activity and therefore of tempering the excitotoxic 'risk' that elevated synaptic glutamate levels otherwise represent. Our observations carry substantial health ramifications because they raise the interesting likelihood that synaptic clearance of glutamate is up-regulated or down-regulated in response to molecular signals acting in or on the astrocyte. This proposal aims at providing mechanistic definition for those regulatory mechanisms.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (01))
Program Officer
May, Michael K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Rochester
Schools of Dentistry
United States
Zip Code
Kimmich, George A; Roussie, James A; Randles, Joan (2002) Aspartate aminotransferase isotope exchange reactions: implications for glutamate/glutamine shuttle hypothesis. Am J Physiol Cell Physiol 282:C1404-13
Kimmich, G A; Roussie, J; Manglapus, M et al. (2001) Characterization of Na+-coupled glutamate/aspartate transport by a rat brain astrocyte line expressing GLAST and EAAC1. J Membr Biol 182:17-30
Wilson, J J; Randles, J; Kimmich, G A (1998) Na+-coupled alanine transport in LLC-PK1 cells: the relationship between the Km for Na+ at low [Alanine] and potential dependence for the system. J Membr Biol 165:275-82
Wilson, J J; Randles, J; Kimmich, G A (1996) A model for the kinetic mechanism of sodium-coupled L-alanine transport in LLC-PK1 cells. Am J Physiol 270:C49-56
Kimmich, G A; Randles, J; Wilson, J (1994) Na(+)-coupled alanine transport in LLC-PK1 cells. Am J Physiol 267:C1119-29
Ronner, P; Higgins, T J; Kimmich, G A (1991) Inhibition of ATP-sensitive K+ channels in pancreatic beta-cells by nonsulfonylurea drug linogliride. Diabetes 40:885-92
Kimmich, G A (1990) Membrane potentials and the mechanism of intestinal Na(+)-dependent sugar transport. J Membr Biol 114:1-27
Kimmich, G A; Randles, J; Anderson, R L (1988) Inhibition of the serosal sugar carrier in isolated intestinal epithelial cells by saccharin. Food Chem Toxicol 26:927-34
Wingrove, T G; Kimmich, G A (1988) Low-affinity intestinal L-aspartate transport with 2:1 coupling stoichiometry for Na+/Asp. Am J Physiol 255:C737-44
Kimmich, G A; Randles, J (1988) Na+-coupled sugar transport: membrane potential-dependent Km and Ki for Na+. Am J Physiol 255:C486-94

Showing the most recent 10 out of 11 publications