From the Ryanodine Receptor to Cardiac Arrhythmias

Abstract

Circ J 2009; 73: 1561 -1567 t is well known that contraction of the heart is signaled by an increase of intracellular calcium concentration ([Ca 2+ ]i) from a resting or diastolic level of approximately 100 nmol/L to peak systolic levels of approximately 1 μmol/L (see References 1-5 for reviews). A major factor determining the strength of the force of contraction is the amplitude of this systolic Ca transient; for example, the positive inotropic effect of β-adrenergic stimulation results from an increase of the amplitude of the systolic Ca transient.There are 2 sources of the calcium that activates contraction: (1) Ca entry from the extracellular environment during the action potential, largely via the L-type Ca current, and (2) Ca released from the intracellular Ca 2+ store, the sarcoplasmic reticulum (SR) ( Figure 1A). In mammalian cardiac muscle, release from the SR accounts for the majority of the Ca required for contraction. The release of Ca 2+ from the SR occurs in response to a small increase of Ca 2+ concentration immediately adjacent to the SR Ca 2+ release channel, the ryanodine receptor (RyR). This initial increase of [Ca 2+ ]i is due to Ca 2+ entering the cell during the action potential on the L-type Ca 2+ current. As the release process is Ca 2+ dependent, it is termed Ca 2+ -induced Ca 2+ release (CICR). The opening of individual clusters of RyRs can be observed from the resulting brief increases of [Ca 2+ ]i and have been termed "Ca sparks". 6 Ordinarily, all the SR Ca 2+ release units are synchronized to release Ca 2+ "simultaneously" to produce the systolic rise of [Ca 2+ ]i. 7 Although there are significant functional, structural and molecular differences between atrial and ventricular myocytes that result in differences in the spatiotemporal properties of the systolic Ca 2+ transient, [8][9][10] the SR is still the main source of Ca 2+ in the atria. 11 As well as being activated and regulated by cytoplasmic Ca, opening of the RyR is also increased by an increase of the Ca concentration in the SR (so called "luminal" Ca). [12][13][14] As a consequence, an increase of luminal Ca leads to an increase of the amplitude of the systolic Ca transient ( Figure 1B). [15][16][17] This relationship between SR Ca content and systolic Ca has both physiological and pathological consequences. Physiologically, it contributes to the positive inotropic effects of SERCA stimulation during β-adrenergic stimulation 18 or increases of heart rate. 19,20 One pathological consequence is seen in heart failure, in which a decrease of SR Ca content results in a decrease of the amplitude of the systolic Ca transient. [21][22][23] Quantitative analysis has shown that in heart disease the fractional decrease of the systolic Ca transient is greater than that of the SR Ca content, 23 a result that is to be expected from the steep dependence of Ca release on SR Ca content. 17,24 Calcium Overload and WavesCircumstances that increase the amount of Ca in the SR excessively result in a situation known as "calcium overload". Th...

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