The calcium response to the excitotoxin kainate is amplified by subsequent reduction of extracellular sodium.
The relation between intracellular and extracellular [Na+] and [Ca2+] and membrane potential during stimulation of non-N-methyl-D-aspartate glutamate receptors has been studied in cerebellar granule cells using the fluorescent indicators SBFI, fura-2 and the bisoxonol membrane potential probe DiBaC4(3). Kainate increased both [Ca2+]i (intracellular [Ca2+]) and [Na+]i (intracellular [Na+]) and depolarized the membrane. This elevation of [Ca2+]i was only partially dependent on the presence of extracellular Na+ at the time of kainate addition. Removal of extracellular Na+ itself had a very minor effect on the [Ca2+]i or membrane potential of unstimulated cells. If extracellular Na+ was removed (in order to reverse the [Na+] gradient) or its concentration reduced during stimulation with kainate, the membrane depolarization recovered as expected. However, the intracellular level of sodium recovered only very slowly and the [Ca2+]i rose sharply, rather than recovering as might be expected on repolarization of depolarized cells possessing voltage sensitive calcium channels. This effect of extracellular [Na+] reduction on [Ca2+]i was mimicked by ouabain, another agent that causes accumulation of [Na+] in cells. These results suggest that Na+/Ca2+ exchange may play a major role in calcium homeostasis in stimulated cells, and that the levels of Na+ inside and outside the cell are critical in determining the effect of receptor stimulation on the intracellular [Ca2+].
Department of Biochemistry and Pharmacy, Abo Akademi University BioCity, Turku, Finland.
M J
MJ
Courtney
M O
MO
Enkvist
K E
KE
Akerman
D000818:Animals; D001572:Benzofurans; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D004988:Ethers, Cyclic; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes; D016257:Fura-2; D006706:Homeostasis / Q000187:drug effects; D007608:Kainic Acid / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism / Q000502:physiology*
D001572:Benzofurans; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002316:Cardiotonic Agents; D004988:Ethers, Cyclic; D018690:Excitatory Amino Acid Agonists; D005456:Fluorescent Dyes; D017470:Receptors, Glutamate; C061665:sodium-binding benzofuran isophthalate; D010042:Ouabain; D012964:Sodium; D009543:Nifedipine; D007608:Kainic Acid; D002118:Calcium; D016257:Fura-2