Subunit-specific modulation of T-type calcium channels by zinc.
Zinc (Zn2+) functions as a signalling molecule in the nervous system and modulates many ionic channels. In this study, we have explored the effects of Zn2+ on recombinant T-type calcium channels (CaV3.1, CaV3.2 and CaV3.3). Using tsA-201 cells, we demonstrate that CaV3.2 current (IC50, 0.8 microm) is significantly more sensitive to Zn2+ than are CaV3.1 and CaV3.3 currents (IC50, 80 microm and approximately 160 microm, respectively). This inhibition of CaV3 currents is associated with a shift to more negative membrane potentials of both steady-state inactivation for CaV3.1, CaV3.2 and CaV3.3 and steady-state activation for CaV3.1 and CaV3.3 currents. We also document changes in kinetics, especially a significant slowing of the inactivation kinetics for CaV3.1 and CaV3.3, but not for CaV3.2 currents. Notably, deactivation kinetics are significantly slowed for CaV3.3 current (approximately 100-fold), but not for CaV3.1 and CaV3.2 currents. Consequently, application of Zn2+ results in a significant increase in CaV3.3 current in action potential clamp experiments, while CaV3.1 and CaV3.2 currents are significantly reduced. In neuroblastoma NG 108-15 cells, the duration of CaV3.3-mediated action potentials is increased upon Zn2+ application, indicating further that Zn2+ behaves as a CaV3.3 channel opener. These results demonstrate that Zn2+ exhibits differential modulatory effects on T-type calcium channels, which may partly explain the complex features of Zn2+ modulation of the neuronal excitability in normal and disease states.
Traboulsie
Achraf
A
Département de Physiologie, Institut de Génomique Fonctionnelle (IGF), CNRS UMR 5203, INSERM U661, Universités de Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier cedex 05, France.
Chemin
Jean
J
Chevalier
Marc
M
Quignard
Jean-François
JF
Nargeot
Joël
J
Lory
Philippe
P
D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D004594:Electrophysiology; D006801:Humans; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins; D009435:Synaptic Transmission / Q000187:drug effects; D013788:Thalamus / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D015032:Zinc / Q000494:pharmacology*
C121855:CACNA1G protein, human; C479952:CACNA1H protein, human; C469757:CACNA1I protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D026901:Membrane Transport Proteins; D011994:Recombinant Proteins; D015032:Zinc