title: Mechanism of the persistent sodium current activator veratridine-evoked Ca elevation: implication for epilepsy.
abstract: Although the role of Na(+) in several aspects of Ca(2+) regulation has already been shown, the exact mechanism of intracellular Ca(2+) concentration ([Ca(2+)](i)) increase resulting from an enhancement in the persistent, non-inactivating Na(+) current (I(Na,P)), a decisive factor in certain forms of epilepsy, has yet to be resolved. Persistent Na(+) current, evoked by veratridine, induced bursts of action potentials and sustained membrane depolarization with monophasic intracellular Na(+) concentration ([Na(+)](i)) and biphasic [Ca(2+)](i) increase in CA1 pyramidal cells in acute hippocampal slices. The Ca(2+) response was tetrodotoxin- and extracellular Ca(2+)-dependent and ionotropic glutamate receptor-independent. The first phase of [Ca(2+)](i) rise was the net result of Ca(2+) influx through voltage-gated Ca(2+) channels and mitochondrial Ca(2+) sequestration. The robust second phase in addition involved reverse operation of the Na(+)-Ca(2+) exchanger and mitochondrial Ca(2+) release. We excluded contribution of the endoplasmic reticulum. These results demonstrate a complex interaction between persistent, non-inactivating Na(+) current and [Ca(2+)](i) regulation in CA1 pyramidal cells. The described cellular mechanisms are most likely part of the pathomechanism of certain forms of epilepsy that are associated with I(Na,P). Describing the magnitude, temporal pattern and sources of Ca(2+) increase induced by I(Na,P) may provide novel targets for antiepileptic drug therapy.
authors.affiliation: Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Szigony, Hungary.
authors.forename: Adám
authors.initials: A
authors.lastname: Fekete
authors.forename: Laura
authors.initials: L
authors.lastname: Franklin
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikemoto
authors.forename: Balázs
authors.initials: B
authors.lastname: Rózsa
authors.forename: Balázs
authors.initials: B
authors.lastname: Lendvai
authors.forename: E
authors.initials: E
authors.lastname: Sylvester Vizi
authors.forename: Tibor
authors.initials: T
authors.lastname: Zelles
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D001703:Biophysics; D019256:Cadmium Chloride / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007476:Ionophores; D026941:Sodium Channel Blockers; D013841:Thiazepines; D013779:Tetrodotoxin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D002998:Clonazepam; D019284:Thapsigargin; D014701:Veratridine; C079032:CGP 37157; D012964:Sodium; D019256:Cadmium Chloride; D002118:Calcium