Zn(2+) slows down Ca(V)3.3 gating kinetics: implications for thalamocortical activity.
We employed whole cell patch-clamp recordings to establish the effect of Zn(2+) on the gating the brain specific, T-type channel isoform Ca(V)3.3 expressed in HEK-293 cells. Zn(2+) (300 microM) modified the gating kinetics of this channel without influencing its steady-state properties. When inward Ca(2+) 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, Zn(2+) slowed down channel deactivation but channel recovery from inactivation was only modestly changed. Zn(2+) also decreased whole cell Ca(2+) permeability to 45% of control values. In the presence of Zn(2+), Ca(2+) 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 Zn(2+) on T-type channels (while leaving the kinetic parameters of voltage-gated Na(+) and K(+) unchanged) revealed that Zn(2+) 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 Zn(2+) decreased the frequency of occurrence of ictal-like epileptiform discharges in rat thalamocortical slices perfused with medium containing the convulsant 4-aminopyridine (50 microM). These data demonstrate that Zn(2+) modulates Ca(V)3.3 channel gating thus leading to increased neuronal excitability. We also propose that endogenous Zn(2+) may have a role in controlling thalamocortical oscillations.
Cataldi
M
M
Divisione di Farmacologia, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, Naples, Italy.
Lariccia
V
V
Marzaioli
V
V
Cavaccini
A
A
Curia
G
G
Viggiano
D
D
Canzoniero
L M T
LM
di Renzo
G
G
Avoli
M
M
Annunziato
L
L
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000465:Algorithms; D000818:Animals; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013788:Thalamus / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D015032:Zinc / Q000494:pharmacology*
C469757:CACNA1I protein, human; D020747:Calcium Channels, T-Type; D002614:Chelating Agents; D026901:Membrane Transport Proteins; D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D015032:Zinc