Calcium Buffering in the Heart in Health and Disease

Figures

• 

  Figure 1.. Chemistry of Ca2+ binding to buffers. A, Schematics showing Ca2+ in various environments: water (i), bound to EDTA (ii), and bound to an EF hand (iii). B, Reaction schemes for Ca2+ binding to various buffers: simple binding (i), competition with Mg2+ (ii), and competition with protons (iii).

• 

  Figure 2.. Properties of cellular cardiac Ca2+ buffers. Ai, Steady-state Ca2+ buffering showing the dependence of bound on free Ca2+. The colored curves show the contributions of the 2 Ca2+ binding sites (regulatory [Reg] and Mg) of TnC, myosin, and SERCA. The solid black line shows the total, calculated as the sum of these components and the others listed in the Table. The dotted black line represents the sum of the fast buffers (top part of Table). ii, Buffer power (calculated as in equation 2) as a function of [Ca2+]i. B, Time course of change of bound [Ca2+] in response to systolic Ca2+ transients applied at 1.5 Hz. i, Absolute levels of [Ca2+]. The dashed line shows free [Ca2+] and the colored traces show the concentration of the Ca2+-bound form of the various ligands. ii, Normalized concentrations to emphasize kinetics. C, The change of bound Ca2+ in response to a series of Ca2+ transients (not shown) applied at 1.5 Hz. SERCA indicates sarcoplasmic reticulum Ca2+ ATPase pump; and TnC, troponin C.

• 

  Figure 3.. Measurement of buffering in intact cells. A, Comparison of the effects of Ca2+ influx through the L-type Ca2+ channel (bottom) with the resulting increase of [Ca2+]i. B, Relationship between the integral of the L-type Ca2+ current and the change of [Ca2+]i. Ca2+ removal by SR, mitochondria, NCX, and PMCA were inhibited with thapsigargin, a mitochondrial uncoupler, Na-free solution and elevated external Ca2+ concentration, respectively. Figure reproduced from Bers35 from an original article34 with permission. Copyright © 2001, Kluwer Academic. C, Determination of Ca2+ buffering from the caffeine-evoked release of Ca2+ from the SR. Traces show (from top to bottom): [Ca2+]i, NCX current, integral of current. Caffeine (10 mmol/L) was applied as shown by the bar. D, Relationship between total Ca2+ (estimated from the integral of NCX current) and [Ca2+]i. E, Separation of buffering into total, the contribution from the Ca-sensitive indicator (fluo-3) and the calculated intrinsic buffering of the cytoplasm. Reproduced from Trafford et al.36 NCX indicates sodium calcium exchange; PMCA, plasma membrane Ca2+ ATPase; and SR, sarcoplasmic reticulum.

• 

  Figure 4.. Effects of [Ca2+]i and buffer Kd on buffer power. A, Effects of [Ca2+]. The top graph shows fractional saturation of a single buffer as a function of [Ca2+]. Curves are shown for 3 different values of Kd. The lower graph shows calculated buffer power (change of total Ca2+/change of [Ca2+]i) as a function of [Ca2+] for these values of Kd. Colors correspond to those above. B, Dependence of buffer power on Kd at the 3 values of [Ca2+] indicated. C, The effects of a small increase of diastolic [Ca2+]i on the change of systolic [Ca2+]i produced by the addition of a fixed amount of total [Ca2+]. The buffer curve (fast buffers only) shows 2 levels of diastolic [Ca2+]i indicated as ad (50 nmol/L) and bd (150 nmol/L). The systolic levels (respectively, as and bs) are obtained by adding 60 µmol/L total [Ca2+] resulting in a larger increase of systolic [Ca2+]i in b compared with a. D, Simulation of the effect of adding and removing 60 µmol/L total Ca2+ with kinetics designed to represent a Ca2+ transient. Labels correspond to points in C. Upper, simulated Ca2+ transients; Lower, predicted force responses calculated using a published model.53

• 

  Figure 5.. Effects of altered buffer power. A, Abolition of centripetal propagation of the Ca2+ transient by rapid atrial pacing (RAP). Upper traces are linescan images. Lower records show [Ca2+]i measured at surface of cell (black) and in center (green). Left, Records from control. Right, Records after rapid stimulation. Reproduced from.71 B, Relaxation of contraction in isolated rat myocytes. Records show control (euthyroid), hypothyroid, and hypothyroid with parvalbumin expressed by gene transfer. Reproduced from.72 C, Left, comparison of the effects of the I79N mutation of troponin T with that of the Ca2+ sensitizing agent EMD 57033 on the relationship between pCa and force. Right, Effects of EMD 57033 on the occurrence of ventricular tachycardia (VT). Reproduced from Greiser et al.73