Abstract
Ryanodine receptors (RyRs) and inositol triphosphate receptors (InsP3Rs) are structurally related intracellular calcium release channels that participate in multiple primary or secondary amplified Ca2+ signals, triggering muscle contraction and oscillatory Ca2+ waves, or activating transcription factors. In the heart, RyRs play an indisputable role in the process of excitation–contraction coupling as the main pathway for Ca2+ release from sarcoplasmic reticulum (SR), and a less prominent role in the process of excitation–transcription coupling. Conversely, InsP3Rs are believed to contribute in subtle ways, only, to contraction of the heart, and in more important ways to regulation of transcription factors. Because uncontrolled activity of either RyRs or InsP3Rs may elicit life-threatening arrhythmogenic and/or remodeling Ca2+ signals, regulation of their activity is of paramount importance for normal cardiac function. Due to their structural similarity, many regulatory factors, accessory proteins, and post-translational processes are equivalent for RyRs and InsP3Rs. Here we discuss regulation of RyRs and InsP3Rs by CaMKII phosphorylation, but touch on other kinases whenever appropriate. CaMKII is emerging as a powerful modulator of RyR and InsP3R activity but interestingly, some of the complexities and controversies surrounding phosphorylation of RyRs also apply to InsP3Rs, and a clear-cut effect of CaMKII on either channel eludes investigators for now. Nevertheless, some effects of CaMKII on global cellular activity, such as SR Ca2+ leak or force-frequency potentiation, appear clear now, and this constrains the limits of the controversies and permits a more tractable approach to elucidate the effects of phosphorylation at the single channel level.
Highlights
Ryanodine receptors (RyRs) and inositol triphosphate receptors (InsP3Rs) are structurally related intracellular calcium release channels that participate in multiple primary or secondary amplified Ca2+ signals, triggering muscle contraction and oscillatory Ca2+ waves, or activating transcription factors
Since the study by Marx et al (2000) reporting that S2808 was hyperphosphorylated in heart failure patients and that its phosphorylation enhanced dramatically the activity of RyR2 channels, several groups have studied this phospho-site in detail (Jiang et al, 2002; Rodriguez et al, 2003; Stange et al, 2003; Currie et al, 2004; Ai et al, 2005; Xiao et al, 2005; Carter et al, 2006; Kohlhaas et al, 2006; Huke and Bers, 2008; MacDonnell et al, 2008; Fischer et al, 2013), with the majority of evidence pointing to S2808 being a target for protein kinase A (PKA), CaMKII and possibly PKG
To what extent are CaMKII and RyR2 channels responsible for these effects? We examined in preceding paragraphs that, the precise transduction pathways have not been completely elucidated yet, it is clear that CaMKII is activated upon β-adrenergic stimulation of the heart
Summary
Ryanodine receptors (RyRs) and inositol triphosphate receptors (InsP3Rs) are structurally related intracellular calcium release channels that participate in multiple primary or secondary amplified Ca2+ signals, triggering muscle contraction and oscillatory Ca2+ waves, or activating transcription factors.
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