The Journal of Neurophysiology Vol. 81 No. 4 April 1999, pp. 1506-1512
Copyright ©1999 by the American Physiological Society

Subtype-Specific Effects of Lithium on Glutamate Receptor Function

 ¹Department of Neuroscience and  ²Department of Pharmacology and Therapeutics, University of Florida Medical College, J. H. Miller Health Center, Gainesville, Florida 32610-0267

Karkanias, Nikolas B. and Roger L. Papke. Subtype-specific effects of lithium on glutamate receptor function. We report that substitution of sodium with lithium (Li⁺) in the extracellular solution causes subtype-specific changes in the inward and outward currents of glutamate receptors (GluRs), without a shift in reversal potential. Li⁺ produces an increase of inward and outward currents of -amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors and decreases in the currents of kainate (KA) and N-methyl-D-aspartate receptors. The greatest effect of Li⁺ was observed with GluR3. A concentration-response curve for GluR3 reveals that the potentiation caused by Li⁺ is greatest at saturating agonist concentrations. GluR1, which shows no potentiation by Li⁺ at 100 µM KA, shows a small but significant potentiation at saturating KA and glutamate concentrations. The effects of Li⁺ on outward current, where Li⁺ is not the primary charge carrier, and the lack of reversal potential shift argue for a mechanism of potentiation not associated with Li⁺ permeation. This potentiation of current is specific for Li⁺ because rubidium, although causing an increase of inward current, shifted the reversal potential and did not increase outward current. The effects of Li⁺ are different for KA, a weak desensitizing agonist, and glutamate, a strong desensitizing agonist, suggesting that Li⁺ might interact with a mechanism of desensitization. By using cyclothiazide (CTZ) to reduce desensitization of GluR3, we find that for low concentrations of KA and glutamate potentiation of the response by a combination of CTZ and Li⁺ is no greater than by CTZ or Li⁺ alone. However, at high concentrations of agonist, the potentiation of the response by a combination of CTZ and Li⁺ is significantly greater than by CTZ or Li⁺ alone. This potentiation was additive for glutamate but not for KA. At high agonist concentration in the presence of CTZ, the intrinsically lower desensitization produced with KA-evoked responses may preclude Li⁺ from potentiating the current to the same degree as it can potentiate glutamate-evoked responses. The additive effects of CTZ and Li⁺ were unique to the flop variant of GluR3.