The function and regulation of calsequestrin-2: implications in calcium-mediated arrhythmias

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.

The online version contains supplementary material available at 10.1007/s12551-021-00914-6.