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This Article Full Text Full Text (PDF) All Versions of this Article: 98/4/2274    most recent 00889.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Cataldi, M. Articles by Annunziato, L. Search for Related Content PubMed PubMed Citation Articles by Cataldi, M. Articles by Annunziato, L.

Zn²⁺ Slows Down Ca_V3.3 Gating Kinetics: Implications for Thalamocortical Activity

¹Divisione di Farmacologia, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, Naples, Italy; ²Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; and ³Dipartimento di Medicina Sperimentale, Prima Facoltà di Medicina e Chirurgia, Università di Roma Sapienza, Rome, Italy

Submitted 21 August 2006; accepted in final form 15 August 2007

We employed whole cell patch-clamp recordings to establish the effect of Zn²⁺ on the gating the brain specific, T-type channel isoform Ca_V3.3 expressed in HEK-293 cells. Zn²⁺ (300 µM) modified the gating kinetics of this channel without influencing its steady-state properties. When inward Ca²⁺ currents were elicited by step depolarizations at voltages above the threshold for channel opening, current inactivation was significantly slowed down while current activation was moderately affected. In addition, Zn²⁺ slowed down channel deactivation but channel recovery from inactivation was only modestly changed. Zn²⁺ also decreased whole cell Ca²⁺ permeability to 45% of control values. In the presence of Zn²⁺, Ca²⁺ currents evoked by mock action potentials were more persistent than in its absence. Furthermore, computer simulation of action potential generation in thalamic reticular cells performed to model the gating effect of Zn²⁺ on T-type channels (while leaving the kinetic parameters of voltage-gated Na⁺ and K⁺ unchanged) revealed that Zn²⁺ increased the frequency and the duration of burst firing, which is known to depend on T-type channel activity. In line with this finding, we discovered that chelation of endogenous Zn²⁺ decreased the frequency of occurrence of ictal-like epileptiform discharges in rat thalamocortical slices perfused with medium containing the convulsant 4-aminopyridine (50 µM). These data demonstrate that Zn²⁺ modulates Ca_V3.3 channel gating thus leading to increased neuronal excitability. We also propose that endogenous Zn²⁺ may have a role in controlling thalamocortical oscillations.