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J Physiol Volume 512, Number 3, 677-691, November 1, 1998
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The Journal of Physiology (1998), 512.3, pp. 677-691
© Copyright 1998 The Physiological Society

Direct measurement of SR release flux by tracking 'Ca2+ spikes' in rat cardiac myocytes

Long-Sheng Song, James S. K. Sham *, Michael D. Stern, Edward G. Lakatta and Heping Cheng

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224 and * Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA

  1. Ca2+ release flux across the sarcoplasmic reticulum (SR) during cardiac excitation-contraction coupling was investigated using a novel fluorescence method. Under whole-cell voltage-clamp conditions, rat ventricular myocytes were dialysed with a high concentration of EGTA (4·0 mM, 150 nM free Ca2+), to minimize the residence time of released Ca2+ in the cytoplasm, and a low-affinity, fast Ca2+ indicator, Oregon Green 488 BAPTA-5N (OG-5N; 1·0 mM, Kd equv 31 µM), to optimize the detection of localized high [Ca2+] in release site microdomains. Confocal microscopy was employed to resolve intracellular [Ca2+] at high spatial and temporal resolution.

  2. Analytical and numerical analyses indicated that, under conditions of high EGTA concentration, the free [Ca2+] change is the sum of two terms: one major term proportional to the SR release flux/Ca2+ influx, and the other reflecting the running integral of the released Ca2+.

  3. Indeed, the OG-5N transients in EGTA-containing cells consisted of a prominent spike followed by a small pedestal. The OG-5N spike closely resembled the first derivative (d[Ca2+]/dt) of the conventional Ca2+ transient (with no EGTA), and mimicked the model-derived SR Ca2+ release function reported previously. In SR Ca2+-depleted cells, the OG-5N transient also closely followed the waveform of L-type Ca2+ current (ICa). Using ICa as a known source of Ca2+ influx, SR flux can be calibrated in vivo by a linear extrapolation of the ICa-elicited OG-5N signal.

  4. The OG-5N image signal was localized to discrete release sites at the Z-line level of sarcomeres, indicating that the local OG-5N spike arises from 'Ca2+ spikes' at transverse (T) tubule-SR junctions (due to the imbalance between calcium ions entering the cytosol and the buffer molecules).

  5. Both peak SR release flux and total amount of released Ca2+ exhibited a bell-shaped voltage dependence. The temporal pattern of SR release also varied with membrane voltage: Ca2+ release was most synchronized and produced maximal peak release flux (4·2 mM s-1) at 0 mV; in contrast, maximal total release occurred at -20 mV (71 versus 61 µM at 0 mV), but the localized release signals were partially asynchronous. Since the maximal conventional [Ca2+] transient and contraction were elicited at 0 mV, it appears that not only the amount of Ca2+ released, but also the synchronization among release sites affects the whole-cell Ca2+ transient and the Ca2+-myofilament interaction.



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