Cytosolic zinc release and clearance in hippocampal neurons exposed to glutamate--the role of pH and sodium.
Although Zn(2+) homeostasis in neurons is tightly regulated and its destabilization has been linked to a number of pathologies including Alzheimer's disease and ischemic neuronal death, the primary mechanisms affecting intracellular Zn(2+) concentration ([Zn(2+) ](i)) in neurons exposed to excitotoxic stimuli remain poorly understood. The present work addressed these mechanisms in cultured hippocampal neurons exposed to glutamate and glycine (Glu/Gly). [Zn(2+)](i) and intracellular Ca(2+) concentration were monitored simultaneously using FluoZin-3 and Fura-2FF, and intracellular pH (pH(i)) was studied in parallel experiments using 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein. Glu/Gly applications under Na(+)-free conditions (Na(+) substituted with N-methyl-D-glucamine(+)) caused Ca(2+) influx, pH(i) drop, and Zn(2+) release from intracellular stores. Experimental maneuvers resulting in a pH(i) increase during Glu/Gly applications, such as stimulation of Na(+) -dependent pathways of H(+) efflux, forcing H(+) efflux via gramicidin-formed channels, or increasing extracellular pH counteracted [Zn(2+)](i) elevations. In the absence of Na(+), the rate of [Zn(2+)](i) decrease could be correlated with the rate of pH(i) increase. In the presence of Na(+), the rate of [Zn(2+) ](i) decrease was about twice as fast as expected from the rate of pH(i) elevation. The data suggest that Glu/Gly-induced cytosolic acidification promotes [Zn(2+) ](i) elevations and that Na(+) counteracts the latter by promoting pH(i)-dependent and pH(i)-independent mechanisms of cytosolic Zn(2+) clearance.
Department of Psychiatry, The Psychiatric Institute, The University of Illinois at Chicago, Chicago, Illinois 60612, USA. lkiedr@psych.uic.edu
Lech
L
Kiedrowski
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D004622:Embryo, Mammalian; D005029:Ethylenediamines / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D016257:Fura-2 / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology*; D011083:Polycyclic Compounds / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D018709:Statistics, Nonparametric; D015032:Zinc / Q000378:metabolism*
D002614:Chelating Agents; D005029:Ethylenediamines; D018690:Excitatory Amino Acid Agonists; C451182:FluoZin-3; D011083:Polycyclic Compounds; D018698:Glutamic Acid; D016202:N-Methylaspartate; D004492:Edetic Acid; D012964:Sodium; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D002118:Calcium; D005998:Glycine; D016257:Fura-2
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