Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart

Abstract

Central to controlling intracellular calcium concentration ([Ca 2+] i ) are a number of Ca 2+ transporters and channels with the L-type Ca 2+ channel, Na +–Ca 2+ exchanger and sarcoplasmic reticulum Ca 2+-ATPase (SERCA) being of particular note in the heart. This review concentrates on the regulation of [Ca 2+] i in cardiac muscle and the homeostatic mechanisms employed to ensure that the heart can operate under steady-state conditions on a beat by beat basis. To this end we discuss the relative importance of various sources and sinks of Ca 2+ responsible for initiating contraction and relaxation in cardiac myocytes and how these can be manipulated to regulate the Ca 2+ content of the major Ca 2+ store, the sarcoplasmic reticulum (SR). We will present a simple feedback system detailing how such control can be achieved and highlight how small perturbations to the steady-state operation of the feedback loop can be both beneficial physiologically and underlie changes in systolic Ca 2+ in ageing and heart disease. In addition to manipulating the amplitude of the normal systolic Ca 2+ transient, the tight regulation of SR Ca 2+ content is also required to prevent the abnormal, spontaneous or diastolic release of Ca 2+ from the SR. Such diastolic events are a major factor contributing to the genesis of cardiac arrhythmias in disease situations and in recently identified familial mutations in the SR Ca 2+ release channel (ryanodine receptor, RyR). How such diastolic release arises and potential mechanisms for controlling this will be discussed.