Ca2+ permeation through Na+ channels in guinea pig ventricular myocytes.
This study was undertaken to test the hypothesis that, in the absence of extracellular Na+, Ca2+ can permeate tetrodotoxin (TTX)-sensitive Na+ channels in Cs(+)-loaded whole cell voltage-clamped guinea pig ventricular myocytes (22-24 degrees C). With 10 mM extracellular Ca2+, 50-ms step depolarizations (-50 to +25 mV) from holding potentials of -100 or -80 mV elicited fast and slow types of inward current: 1) a small (< 400 pA) dihydropyridine-insensitive inward current that exhibited similar voltage dependence to that of Na+ channels, with an activation threshold and peak near -45 mV and -30 mV, respectively; and 2) a larger and slower L-type Ca2+ current that activated and peaked at more positive potentials. Extracellular replacement of Ca2+ by Mg2+ abolished both currents. The lack of sensitivity of the low-threshold Ca(2+)-current amplitude to 50 or 200 microM Ni2+ suggests that this current is not produced by T-type Ca2+ current. In contrast, TTX dose dependently inhibited the low-threshold Ca2+ current, with a half-maximal inhibition concentration of 2.4 microM. Veratridine (10-50 microM), a plant alkaloid that alters the gating and permeability properties of Na+ current, induced an outward shift of time-dependent current during steps to -25 mV and typical slowly decaying inward tail currents after repolarization to -80 mV. Cell exposure to 10 and 50 microM extracellular Na+ inhibited the inward current by 21.2 +/- 3.9% (n = 23) and 14.0 +/- 3.0% (n = 14), respectively, whereas 1 microM Na+ (n = 14) was without effect. The application of 200 microM Na+ produced a small enhancement of the current (+6.2 +/- 4.1%; n = 14) which was just at the limit of significance. Our data support the notion that Ca2+ can permeate cardiac Na+ channels in the absence of an agonist and external Na+.
Cole
W C
WC
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Alberta, Canada.
Chartier
D
D
Martin
M
M
Leblanc
N
N
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009532:Nickel / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
D015220:Calcium Channels; D015222:Sodium Channels; D013779:Tetrodotoxin; D009532:Nickel; D012964:Sodium; D002118:Calcium