Mechanism and regulation of Na+-coupled transport of neurotransmitters in the CNS.
Neurotransmitter molecules released from presynaptic neuronal stores act on post-synaptic neuronal receptors. Action of most transmitters is terminated when they are sequestered in glial and neuronal cells near the synapse following transmitter uptake by Na+-coupled transport systems. Efficient function of the relevant transport systems is imperative for keeping extracellular concentrations of transmitters low (~ 1 uM) so that the nervous system remains poised for further transmission of excitatory and inhibitory signals. Compromised function of neurotransmitter transport systems often occurs concomitantly with various neurodegenerative diseases, although it can be difficult to discern whether compromised function is a cause or a result of the pathophysiological condition. Some aspects of CNS pathophysiology are known to occur because glutamate, the most abundant excitatory transmitter, becomes a potent neurotoxin if it remains in the synapse for even short intervals following its release from the presynaptic neuron.

Our current projects focus on characterizing the function and regulation of Na+-coupled glutamate transporters in astrocytic glial cells. Presynaptic neurons do not have capability for resynthesis of glutamate from glycolytic intermediates, so carbon equivalent to that captured by astrocytes as glutamate must be returned to the neuron by some alternative route, and in some form that avoids activation of neuronal glutamate receptors during the return trip. The return of carbon from astrocytes must also occur at rates sufficient to sustain neuronal synthesis and repackaging of glutamate for subsequent reuse as a transmitter. Although it is recognized that net transfer of metabolites must occur across the glial cell membrane in both directions to accommodate CNS function, details regarding the precise pathway followed during the neuronal/glial/neuronal carbon cycle are not well understood.

Work is also in progress aimed at defining the role that protein kinase C (PKC) plays in regulating function of various CNS transport systems involved in the carbon shuttle. Activation of PKC causes a pronounced increase in glutamate transport capability by cultured astrocytes. We are exploring the mechanism by which PKC modulates astrocytic glutamate transport and metabolism.

• Kimmich GA, Roussie JA, Randles J. Aspartate aminotransferase isotope exchange reactions: implications for glutamate/glutamine shuttle hypothesis. Am J Physiol Cell Physiol. 2002 Jun; 282(6):C1404-13.
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• Kimmich GA, Roussie J, Manglapus M, Randles J. Characterization of Na+-coupled glutamate/aspartate transport by a rat brain astrocyte line expressing GLAST and EAAC1. J Membr Biol. 2001 Jul 1; 182(1):17-30.
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• Wilson JJ, Randles J, Kimmich GA. 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. 1998 Oct 1; 165(3):275-82.
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• Bennett E, Kimmich GA. The molecular mechanism and potential dependence of the Na+/glucose cotransporter. Biophys J. 1996 Apr; 70(4):1676-88.
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• Wilson JJ, Randles J, Kimmich GA. A model for the kinetic mechanism of sodium-coupled L-alanine transport in LLC-PK1 cells. Am J Physiol. 1996 Jan; 270(1 Pt 1):C49-56.
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• Kimmich GA, Randles J, Wilson J. Na(+)-coupled alanine transport in LLC-PK1 cells. Am J Physiol. 1994 Oct; 267(4 Pt 1):C1119-29.
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• Bennett E, Kimmich GA. Na+ binding to the Na(+)-glucose cotransporter is potential dependent. Am J Physiol. 1992 Feb; 262(2 Pt 1):C510-6.
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• Ronner P, Higgins TJ, Kimmich GA. Inhibition of ATP-sensitive K+ channels in pancreatic beta-cells by nonsulfonylurea drug linogliride. Diabetes. 1991 Jul; 40(7):885-92.
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• Kimmich GA, Randles J, Bennett E. Sodium-dependent succinate transport by isolated chick intestinal cells. Am J Physiol. 1991 Jun; 260(6 Pt 1):C1151-7.
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• Kimmich GA. Membrane potentials and the mechanism of intestinal Na(+)-dependent sugar transport. J Membr Biol. 1990 Mar; 114(1):1-27.
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• Smith-Maxwell C, Bennett E, Randles J, Kimmich GA. Whole cell recording of sugar-induced currents in LLC-PK1 cells. Am J Physiol. 1990 Feb; 258(2 Pt 1):C234-42.
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• Kimmich GA. Isolation of intestinal epithelial cells and evaluation of transport functions. Methods Enzymol. 1990; 192:324-40.
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• Kimmich GA, Randles J, Anderson RL. Effect of saccharin on the ATP-induced increase in Na+ permeability in isolated chicken intestinal epithelial cells. Food Chem Toxicol. 1989 Mar; 27(3):143-9.
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• Wingrove TG, Kimmich GA. Low-affinity intestinal L-aspartate transport with 2:1 coupling stoichiometry for Na+/Asp. Am J Physiol. 1988 Dec; 255(6 Pt 1):C737-44.
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• Kimmich GA, Randles J, Anderson RL. Inhibition of the serosal sugar carrier in isolated intestinal epithelial cells by saccharin. Food Chem Toxicol. 1988 Nov-Dec; 26(11-12):927-34.
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• Kimmich GA, Randles J. Na+-coupled sugar transport: membrane potential-dependent Km and Ki for Na+. Am J Physiol. 1988 Oct; 255(4 Pt 1):C486-94.
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• Montrose M, Randles J, Kimmich GA. SITS-sensitive Cl- conductance pathway in chick intestinal cells. Am J Physiol. 1987 Nov; 253(5 Pt 1):C693-9.
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• Wingrove TG, Kimmich GA. High affinity L-aspartate transport in chick small intestine. Am J Physiol. 1987 Jan; 252(1 Pt 1):C105-14.
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• Montrose MH, Kimmich GA. Quantitative use of weak bases for estimation of cellular pH gradients. Am J Physiol. 1986 Mar; 250(3 Pt 1):C418-22.
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• Restrepo D, Kimmich GA. Phlorizin binding to isolated enterocytes: membrane potential and sodium dependence. J Membr Biol. 1986; 89(3):269-80.
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• Kimmich GA, Randles J, Restrepo D, Montrose M. A new method for determination of relative ion permeabilities in isolated cells. Am J Physiol. 1985 May; 248(5 Pt 1):C399-405.
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• Restrepo D, Kimmich GA. Kinetic analysis of mechanism of intestinal Na+-dependent sugar transport. Am J Physiol. 1985 May; 248(5 Pt 1):C498-509.
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• Montrose MH, Bebernitz G, Kimmich GA. Evaluation of ion gradient-dependent H+ transport systems in isolated enterocytes from the chick. J Membr Biol. 1985; 88(1):55-66.
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• Restrepo D, Kimmich GA. Electrical potential dependence of Na+-sugar cotransport determined using TPP+ influx. Ann N Y Acad Sci. 1985; 456:77-9.
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• Kimmich GA, Randles J, Restrepo D, Montrose M. The potential dependence of the intestinal Na+-dependent sugar transporter. Ann N Y Acad Sci. 1985; 456:63-76.
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• Restrepo D, Kimmich GA. The mechanistic nature of the membrane potential dependence of sodium-sugar cotransport in small intestine. J Membr Biol. 1985; 87(2):159-72.
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• Wingrove TG, Kimmich GA. The characterization of intestinal acidic amino-acid transport. Ann N Y Acad Sci. 1985; 456:80-2.
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• Montrose MH, Kimmich GA. Relative rates of Na+-H+ and Cl(-)-OH- exchange reactions in isolated intestinal cells. Ann N Y Acad Sci. 1985; 456:232-4.
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• Hyun CS, Kimmich GA. Interaction of cholera toxin and Escherichia coli enterotoxin with isolated intestinal epithelial cells. Am J Physiol. 1984 Dec; 247(6 Pt 1):G623-31.
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• Kimmich GA, Randles J. Sodium-sugar coupling stoichiometry in chick intestinal cells. Am J Physiol. 1984 Jul; 247(1 Pt 1):C74-82.
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• Kimmich GA, Randles J. An ATP- and Ca2+-regulated Na+ channel in isolated intestinal epithelial cells. Am J Physiol. 1982 Sep; 243(3):C116-23.
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• Hyun CS, Kimmich GA. Effect of cholera toxin on cAMP levels and Na+ influx in isolated intestinal epithelial cells. Am J Physiol. 1982 Sep; 243(3):C107-15.
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• Kimmich GA, Randles J. alpha-Methylglucoside satisfies only Na+-dependent transport system of intestinal epithelium. Am J Physiol. 1981 Nov; 241(5):C227-32.
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• Kimmich GA. Gradient coupling in isolated intestinal cells. Fed Proc. 1981 Aug; 40(10):2474-9.
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• Guillet EG, Kimmich GA. DiO-C3-(5) and DiS-C3-(5): Interactions with RBC, ghosts and phospholipid vesicles. J Membr Biol. 1981 Mar 15; 59(1):1-11.
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• Kimmich GA. The Na+-dependent sugar carrier as a sensor of the cellular electrochemical Na+ potential. Prog Clin Biol Res. 1981; 73:129-42.
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• Kimmich G, Randles J. Regulation of Na+-dependent sugar transport in intestinal epithelial cells by exogenous ATP. Am J Physiol. 1980 May; 238(5):C177-83.
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• Kimmich GA, Randles J. Evidence for an intestinal Na+:sugar transport coupling stoichiometry of 2.0. Biochim Biophys Acta. 1980 Mar 13; 596(3):439-44.
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• Carter-Su C, Kimmich GA. Effect of membrane potential on Na+-dependent sugar transport by ATP-depleted intestinal cells. Am J Physiol. 1980 Mar; 238(3):C73-80.
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• Kimmich GA. Intestinal transport: studies with isolated epithelial cells. Environ Health Perspect. 1979 Dec; 33:37-44.
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• Kimmich GA, Randles J. Energetics of sugar transport by isolated intestinal epithelial cells: effects of cytochalasin B. Am J Physiol. 1979 Jul; 237(1):C56-63.
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• Carter-Su C, Kimmich GA. Membrane potentials and sugar transport by ATP-depleted intestinal cells: effect of anion gradients. Am J Physiol. 1979 Jul; 237(1):C67-74.
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• Kimmich GA, Carter-Su C. Membrane potentials and the energetics of intestinal Na+-dependent transport systems. Am J Physiol. 1978 Sep; 235(3):C73-81.
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• Guillet E, Kimmich G. Differential effects of erythrocyte lysates on spectra of potential-sensing carbocyanine dyes. Biochim Biophys Acta. 1978 May 18; 509(2):385-8.
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• Randles J, Kimmich GA. Effects of phloretin and theophylline on 3-O-methylglucose transport by intestinal epithelial cells. Am J Physiol. 1978 Mar; 234(3):C64-72.
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• Kimmich GA, Randles J. Phloretin-like action of bioflavonoids on sugar accumulation capability of isolated intestinal cells. Membr Biochem. 1978; 1(3-4):221-37.
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• Kimmich GA, Carter-Su C, Randles J. Energetics of Na+-dependent sugar transport by isolated intestinal cells: evidence for a major role for membrane potentials. Am J Physiol. 1977 Nov; 233(5):E357-62.
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• Kimmich GA, Philo RD, Eddy AA. The effects of ionophores on the fluorescence of the cation 3,3'-dipropyloxadicarbocyanine in the presence of pigeon erythrocytes, erythrocyte 'ghosts' or liposomes. Biochem J. 1977 Oct 15; 168(1):81-90.
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• Kimmich GA, Randles J. 2-Deoxyglucose transport by intestinal epithelial cells isolated from the chick. J Membr Biol. 1976 Jun 30; 27(4):363-79.
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• Kimmich GA, Randles J, Brand JS. Assay of picomole amounts of ATP, ADP, and AMP using the luciferase enzyme system. Anal Biochem. 1975 Nov; 69(1):187-206.
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• Kimmich GA, Randles J. A Na+-independent, phloretin-sensitive monosaccharide transport system in isolated intestinal epithelial cells. J Membr Biol. 1975 Aug 11; 23(1):57-76.
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• Peck WA, Messinger K, Kimmich G, Carpenter J. Stimulation of uridine incorporation in isolated bone cells by parathyroid hormone and cyclic AMP. Endocrinology. 1974 Jul; 95(1):289-98.
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• Kimmich GA. Coupling between Na+ and sugar transport in small intestine. Biochim Biophys Acta. 1973 Apr 3; 300(1):31-78.
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• Kimmich GA, Randles J. Interaction between Na+-dependent transport systems for sugars and amino acids. Evidence against a role for the sodium gradient. J Membr Biol. 1973; 12(1):47-68.
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• Tucker AM, Kimmich GA. Characteristics of amino acid accumulation by isolated intestinal epithelial cells. J Membr Biol. 1973; 12(1):1-22.
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• Kimmich GA, Randles J. Effect of K+ and K+ gradients on accumulation of sugars by isolated intestinal epithelial cells. J Membr Biol. 1973; 12(1):23-46.
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• Kimmich GA. Active sugar accumulation by isolated intestinal epithelial cells. A new model for sodium-dependent metabolite transport. Biochemistry. 1970 Sep 15; 9(19):3669-77.
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• Kimmich GA. Preparation and properties of mucosl epithelial cells isolated frmsmall intestine of the chicken. Biochemistry. 1970 Sep 15; 9(19):3659-68.
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• Kimmich GA, Rasmussen H. Regulation of pyruvate carboxylase activity by calcium in intact rat liver mitochondria. J Biol Chem. 1969 Jan 10; 244(1):190-9.
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• Kimmich GA, Rasmussen H. Inhibition of mitochondrial respiration by loss of intra-mitochondrial K+. Biochim Biophys Acta. 1967 May 9; 131(3):413-20.
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• Kimmich GA, Rasmussen H. The effect of parathyroid hormone on mitochondrial ion transport in the terminal portion of the cytochrome chain. Biochim Biophys Acta. 1966 Mar 7; 113(3):457-66.
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• KIMMICH GA, MCCORMICK DB. PAPER CHROMATOGRAPHY OF FLAVIN ANALOGUES. J Chromatogr. 1963 Nov; 12:394-400.
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