Article,

Low efficiency of Ca$^2+$ entry through the Na$^+$-Ca$^2+$ exchanger as trigger for Ca$^2+$ release from the sarcoplasmic reticulum. A comparison between L-type Ca$^2+$ current and reverse-mode Na$^+$-Ca$^2+$ exchange.

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Circ. Res., 81 (6): 1034--1044 (December 1997)

Abstract

It has been proposed that Ca$^2+$ entry through the Na$^+$-Ca$^2+$ exchanger can contribute significantly to the trigger for Ca$^2+$ release from the sarcoplasmic reticulum (SR). We have compared the characteristics of Ca$^2+$ release triggered by reverse-mode Na$^+$-Ca$^2+$ exchange and by L-type Ca$^2+$ current (ICaL) during depolarizing steps in single guinea pig ventricular myocytes (whole-cell voltage clamp, fluo 3 and fura-red as Ca$^2+$i indicators, 36 +/- 1 degrees C, K$^+$-based pipette solution with 20 mmol/L Na$^+$). Conditioning pulses to +60 mV ensured comparable Ca$^2+$ loading of the SR. In the presence of ICaL, Ca$^2+$i transients typically have an early and rapid rising phase reflecting Ca$^2+$ release, which has a bell-shaped voltage dependence with a peak at +10 mV. With Ca$^2+$ entry through Na$^+$-Ca$^2+$ exchange only (20 mumol/L nisoldipine), Ca$^2+$ release flux from the SR is decreased and directly related to the amplitude of the depolarizing step. Ca$^2+$ release is preceded by a significant delay (81 +/- 21 ms at +20 mV, 24 +/- 4 ms at +70 mV) related to Ca$^2+$ entry through the exchanger. Triggered release interrupts Ca$^2+$ entry, as evidenced by reversal of the exchanger current. At potentials positive to +40 mV, Ca$^2+$ influx through Na$^+$-Ca$^2+$ exchange, calculated from the outward exchange current, reaches magnitudes comparable to ICaL, but Ca$^2+$ release due to reverse-mode Na$^+$-Ca$^2+$ exchange still has a significant delay. We calculated trigger efficiency as the ratio between the maximal rate of Ca$^2+$ release and the Ca$^2+$ influx preceding this release; efficiency of reverse-mode Na$^+$-Ca$^2+$ exchange is approximately four times less than that of ICaL. With both ICaL and reverse-mode Na$^+$-Ca$^2+$ exchange present, Ca$^2+$ release is triggered by ICaL, and a contribution of reverse-mode Na$^+$-Ca$^2+$ exchange to the trigger could not be detected at potentials below +60 mV. These characteristics of reverse-mode Na$^+$-Ca$^2+$ exchange predict that its role as a trigger for Ca$^2+$ release during the action potential is likely to be negligible.

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