Large Currents Generate Cardiac Ca 2+ Sparks

Abstract

Previous models of cardiac Ca 2+ sparks have assumed that Ca 2+ currents through the Ca 2+ release units (CRUs) were ∼1–2 pA, producing sparks with peak fluorescence ratio ( F/ F 0) of ∼2.0 and a full-width at half maximum (FWHM) of ∼1 μm. Here, we present actual Ca 2+ sparks with peak F/ F 0 of >6 and a FWHM of ∼2 μm, and a mathematical model of such sparks, the main feature of which is a much larger underlying Ca 2+ current. Assuming infinite reaction rates and no endogenous buffers, we obtain a lower bound of ∼11 pA needed to generate a Ca 2+ spark with FWHM of 2 μm. Under realistic conditions, the CRU current must be ∼20 pA to generate a 2- μm Ca 2+ spark. For currents ≥5 pA, the computed spark amplitudes ( F/ F 0) are large (∼6–12 depending on buffer model). We considered several factors that might produce sparks with FWHM ∼ 2 μm without using large currents. Possible protein–dye interactions increased the FWHM slightly. Hypothetical Ca 2+ “quarks” had little effect, as did blurring of sparks by the confocal microscope. A clusters of CRUs, each producing 10 pA simultaneously, can produce sparks with FWHM ∼ 2 μm. We conclude that cardiac Ca 2+ sparks are significantly larger in peak amplitude than previously thought, that such large Ca 2+ sparks are consistent with the measured FWHM of ∼2 μm, and that the underlying Ca 2+ current is in the range of 10–20 pA.