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 (I_Ca-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⁺ release^2,3. 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 6^th 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).