Chain-reaction Ca(2+) signaling in the heart

Abstract

Mutations in Ca(2+) -handling proteins in the heart have been linked to exercise-induced sudden cardiac death. The best characterized of these have been mutations in the cardiac Ca(2+) release channel known as the ryanodine receptor type 2 (RyR2). RyR2 mutations cause "leaky" channels, resulting in diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) that can trigger fatal cardiac arrhythmias during stress. In this issue of the JCI, Song et al. show that mutations in the SR Ca(2+)-binding protein calsequestrin 2 (CASQ2) in mice result not only in reduced CASQ2 expression but also in a surprising, compensatory elevation in expression of both the Ca(2+)-binding protein calreticulin and RyR2, culminating in premature Ca(2+) release from cardiac myocytes and stress-induced arrhythmia (see the related article beginning on page 1814). In the context of these findings and other recent reports studying CASQ2 mutations, we discuss how CASQ2 influences the properties of Ca(2+)-dependent regulation of RyR2 and how this contributes to cardiac arrhythmogenesis.

Figure 1. Intracellular Ca²⁺ handling in cardiomyocytes.

(A) Calcium transients begin with the initial influx of Ca²⁺ via L-type Ca²⁺ channels followed by Ca²⁺ release from the SR via RyR2s, which culminates in contraction. During relaxation, Ca²⁺ reuptake occurs via the PLN-regulated Ca²⁺ pump SERCA2a. The major Ca²⁺ buffering protein in the SR is CASQ2. High [Ca²⁺]_SR converts monomeric CASQ2 (bound to the RyR2-triadin-junctin complex) to the polymeric CASQ2 form that buffers Ca²⁺ and remains close to the complex in the jSR. Calstabin2 and monomeric CASQ2 bind to the complex and stabilize RyR2 activity. (B) Altered Ca²⁺ handling in CASQ2-deficient myocytes. As Song et al. report (10), in CASQ2-deficient mouse myocytes, RyR2 expression is significantly upregulated and calreticulin abundance is slightly increased. There is a decrease in Ca²⁺ in the SR. Despite altered Ca²⁺ handling in these animals under resting conditions, these compensatory changes in protein expression appear to help maintain relatively normal heart function. However, under catecholamine- or exercise-induced stress, RyR2 instability increases, leading to an increased risk of cardiac arrhythmia. nSR, nonjunctional SR.

Figure 2. Ca²⁺-dependent arrhythmogenesis.

(A) Relationship between [Ca²⁺]_SR and diastolic [Ca²⁺]_i. As [Ca²⁺]_i increases, so does [Ca²⁺]_SR. (B) As [Ca²⁺]_SR increases, so does SR Ca²⁺ leak. Any additional features that increase RyR2 openings (P_o) will also increase Ca²⁺ leak. (C) As leak increases, there is an increasing loss of Ca²⁺ in the SR. (D) Probability of generating a cellular arrhythmia (i.e., a wave) (P_wave). [Ca²⁺]_SR is the primary factor in Ca²⁺ overload arrhythmogenesis because it affects P_o. However, as the leak increases, there is loss of Ca²⁺ from within the SR. Thus, increasing P_o has a biphasic effect on P_wave. The relationship is biphasic because at low P_o, [Ca²⁺]_SR remains sufficiently high to produce substantial Ca²⁺ efflux and sustain the propagation of Ca²⁺ waves. When P_o is very high, the Ca²⁺ leak outpaces SERCA2a; there is a net loss of [Ca²⁺]_SR, and P_wave decreases. Increased SERCA2a activity (red curve) shifts the curve (48). The physiological range occurs at very low RyR2 P_o (about 10^–4 s^–1).