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 alpha-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 microM 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.
Karkanias
N B
NB
Department of Neuroscience, University of Florida Medical College, J. H. Miller Health Center, Gainesville, Florida 32610-0267, USA.
Papke
R L
RL
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology; D001692:Biological Transport / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology*; D007608:Kainic Acid / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000494:pharmacology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012413:Rubidium / Q000493:pharmacokinetics; D012964:Sodium / Q000493:pharmacokinetics; D014982:Xenopus laevis; D000097806:GluK2 Kainate Receptor
D000959:Antihypertensive Agents; D001581:Benzothiadiazines; D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D008094:Lithium; D012333:RNA, Messenger; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D012413:Rubidium; D012964:Sodium; D000097806:GluK2 Kainate Receptor; C104723:glutamate receptor ionotropic, AMPA 3; C104722:glutamate receptor ionotropic, AMPA 2; C004639:cyclothiazide