Changes of SERCA activity have only modest effects on sarcoplasmic reticulum Ca2+ content in rat ventricular myocytes

• Published in: The Journal of physiology 2011-10, Vol.589 (19), p.4723-4729
• Main Authors: Bode, E. F., Briston, S. J., Overend, C. L., O’Neill, S. C., Trafford, A. W., Eisner, D. A.
• Format: Article
• Language: English
• Subjects: Animals; Ca super(2+)-transporting ATPase; Calcium; Calcium (reticular); Calcium - metabolism; Cardiac muscle; Cardiovascular; Heart; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Male; Muscle contraction; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Rats; Rats, Wistar; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - enzymology; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Systole - drug effects; tetracaine; Tetracaine - pharmacology; thapsigargin; Thapsigargin - pharmacology; Ventricle
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2011.211052

Non‐Technical Summary  Cardiac contraction is caused by an increase of calcium (Ca2+) concentration in the cells of the heart, the so‐called ‘systolic Ca2+ transient’. The majority of this Ca2+ is provided by the sarcoplasmic reticulum (SR), which acts as a Ca2+ store within the cell itself. Before the heart can contract again the Ca2+ store needs to be replenished and so Ca2+ is pumped back into the SR by the sarco‐endoplasmic reticulum Ca2+‐ATPase (SERCA). We show that a given fractional decrease of SERCA activity produces a much smaller decrease of SR Ca2+ content. This means that changes of SERCA activity can produce large changes of systolic Ca2+ without the need for energetically expensive alterations of SR Ca2+ content.   Changes of the activity of the sarco‐endoplasmic reticulum Ca2+‐ATPase (SERCA) affect the amplitude of the systolic Ca2+ transient and thence cardiac contractility. This is thought to be due to alterations of SR Ca2+ content. Recent work on mice in which the expression of SERCA is decreased found that a large reduction of SERCA expression resulted in a proportionately much smaller decrease of SR Ca2+ content. The aim of the current work was to investigate the quantitative nature of the dependence of both the amplitude of the systolic Ca2+ transient and SR Ca2+ content on SERCA activity during acute partial inhibition of SERCA. Experiments were performed on rat ventricular myocytes. Brief application of thapsigargin (1 μm) resulted in a decrease of SERCA activity as measured from the rate of decay of the systolic Ca2+ transient. This was accompanied by a decrease in the amplitude of the systolic Ca2+ transient which was linearly related to that of SERCA activity. However, the fractional decrease in the SR Ca2+ content was much less than that of SERCA activity. On average SR Ca2+ content was proportional to SERCA activity raised to the 0.38 ± 0.07 power. This shallow dependence of SR content on SERCA activity arises because Ca2+ release is a steep function of SR Ca2+ content. In contrast SR Ca2+ content was increased 4.59 ± 0.40 (n= 8)‐fold by decreasing ryanodine receptor opening with tetracaine (1 mm). Therefore a modest decrease of SR Ca2+ content results in a proportionately larger fall of Ca2+ release from the SR which can balance a larger initiating decrease of SERCA. In conclusion, the shallow dependence of SR Ca2+ content on SERCA activity is expected for a system in which small changes of SR Ca2+ content produce larger effec