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.
Supplementary information: The online version contains supplementary material available at 10.1007/s12551-021-00914-6.
Keywords: Arrhythmia; Calcium; Calsequestrin-2; Ryanodine receptor.
© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2021.