Calcium homeostasis and arrhythmias

Sarah J. Briston, Jessica D. Clarke, Katharine M. Dibb, Leonie C. Diffley, David A. Eisner, Helen K. Graham, Takeshi Kashimura, Mark A. Richards, Luigi A. Venetucci, Andrew W. Trafford*

Unit of Cardiac Physiology, University of Manchester, Manchester, United Kingdom

*Andrew.Trafford@manchester.ac.uk

Contraction in cardiac muscle is initiated by the systolic rise of intracellular calcium concentration ([Ca2+]i).  The arrival of the action potential results in membrane depolarisation, opening of voltage gated Ca2+ channels (ICa-L) and the entry of a small amount of Ca2+.  This sarcolemmal Ca2+ entry then triggers the release of a much larger amount of Ca2+ from the intracellular Ca2+ store, the sarcoplasmic reticulum (SR) via a process known as Ca2+ induced Ca2+ release (CICR).  The major determinant of the amplitude of the systolic Ca2+ transient and therefore the amplitude of contraction is the amount of Ca2+ that is stored, and therefore releasable from, the SR.  Our previous data has suggested that the relationship between Ca2+ transient amplitude and SR Ca2+ content is cubic1. 

In addition to regulating systolic Ca2+ we also propose that the SR is also a major determinant of the occurrence of arrhythmias.  This arises due to the SR having a finite Ca2+ storage capacity and when SR Ca2+ content exceeds this threshold then Ca2+ is released spontaneously from the SR.  This spontaneous Ca2+ release which occurs in one region of the cell can then propagate as a wave of CICR to all regions of the cell.  Such spontaneous (or diastolic) Ca2+ waves are detrimental to cardiac function from two perspectives; firstly, cells that behave in this manner will not contribute to purposeful contraction and secondly, some of the Ca2+ released in to the cytosol during the diastolic Ca2+ wave will be extruded from the cell by the electrogenic Na+-Ca2+ exchanger thus leading to membrane depolarisation and potentially the onset of arrhythmias.

This presentation will discuss both the control of normal excitation contraction coupling and the mechanisms that are responsible for arrhythmogenic diastolic Ca2+ release.  We will firstly demonstrate that changes of SR Ca2+ content are brought about primarily by the fluxes of Ca2+ across the sarcolemma.  The second part of the presentation will discuss recent controversies regarding the cellular mechanisms responsible for arrhythmogenic diastolic Ca2+ release2,3.  We will conclude by demonstrating that SR Ca2+ content is responsible for whether or not such diastolic Ca2+ release occurs.

This work is supported by The British Heart Foundation and European Union 6th Framework STREP project (Normacor).

References:

 

1.      Trafford, A.W., Díaz, M.E., Eisner, D.A. Coordinated control of cell Ca2+ loading and triggered release from the sarcoplasmic reticulum underlies the rapid inotropic response to increased L-type Ca2+ current. Circ. Res. 88, 195-201 (2001).

2.      Marx, S.O. et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101, 365-376 (2000).

3.      Venetucci, L., Trafford, A.W., Eisner,D.A. Increasing ryanodine receptor open probability alone does not produce arrhythmogenic Ca2+ waves:  threshold Ca2+ content is required. Circ. Res. 100, 105-111 (2007).