Abstract
Cardiac arrhythmias are life-threatening events in which the heart develops an irregular rhythm. Mishandling of Ca2+ within the myocytes of the heart has been widely demonstrated to be an underlying mechanism of arrhythmogenesis. This includes altered function of the ryanodine receptor (RyR2)—the primary Ca2+ release channel located to the sarcoplasmic reticulum (SR). The spontaneous leak of SR Ca2+ via RyR2 is a well-established contributor in the development of arrhythmic contractions. This leak is associated with increased channel activity in response to changes in SR Ca2+ load. RyR2 activity can be regulated through several avenues, including interactions with numerous accessory proteins. One such protein is calsequestrin-2 (CSQ2), which is the primary Ca2+-buffering protein within the SR. The capacity of CSQ2 to buffer Ca2+ is tightly associated with the ability of the protein to polymerise in response to changing Ca2+ levels. CSQ2 can itself be regulated through phosphorylation and glycosylation modifications, which impact protein polymerisation and trafficking. Changes in CSQ2 modifications are implicated in cardiac pathologies, while mutations in CSQ2 have been identified in arrhythmic patients. Here, we review the role of CSQ2 in arrhythmogenesis including evidence for the indirect and direct regulation of RyR2 by CSQ2, and the consequences of a loss of functional CSQ2 in Ca2+ homeostasis and Ca2+-mediated arrhythmias.
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Funding
This work was supported by the Health Research Council of New Zealand [Emerging Researcher First Grant #20/625 to MLM; Project Grants #18/232 and #20/370 to PPJ], the Heart Foundation of New Zealand [Research Fellowship #1784 to MLM; Research Grant #1836 to PPJ] and the Marsden Fund from the Royal Society of New Zealand [Fast-Start Grant #UOO2009 to MLM].
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Sibbles, E.T., Waddell, H.M.M., Mereacre, V. et al. The function and regulation of calsequestrin-2: implications in calcium-mediated arrhythmias. Biophys Rev 14, 329–352 (2022). https://doi.org/10.1007/s12551-021-00914-6
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DOI: https://doi.org/10.1007/s12551-021-00914-6