2020 - Maurocalcin and its analogue MCaE12A facilitate Ca2+ mobilization in cardiomyocytes
CardioExcyte 96 publication in Biochemical Journal (2020)
De Waard S., Montnach J., Cortinovis C., Chkir O., Erfanian M., Hulin P., Gaborit N., Lemarchand P., Mesirca P., Bidaud I., Mangoni M., De Waard M., Ronjat M.
Biochemical Journal (2020) doi: 10.1042/BCJ20200206
Ryanodine receptors are responsible for the massive release of calcium from the 25 sarcoplasmic reticulum that triggers heart muscle contraction. Maurocalcin (MCa) is a 33 26 amino acid peptide toxin known to target skeletal ryanodine receptor. We investigated the 27 effect of MCa and its analogue MCaE12A on isolated cardiac ryanodine receptor (RyR2), and 28 showed that they increase RyR2 sensitivity to cytoplasmic calcium concentrations 29 promoting channel opening and decreases its sensitivity to inhibiting calcium concentrations. By measuring intracellular Ca2+ 30 transients, calcium sparks and contraction 31 on cardiomyocytes isolated from adult rats or differentiated from human induced 32 pluripotent stem cells, we demonstrated that MCaE12A passively penetrates cardiomyocytes 33 and promotes abnormal opening of RyR2. We also investigated the effect of MCaE12A on 34 pacemaker activity of sinus node cells from different mice lines and showed that, MCaE12A 35 improves pacemaker activity of sinus node cells obtained from mice lacking L-type Cav1.3 36 channel, or following selective pharmacologic inhibition of calcium influx via Cav1.3. Our 37 results identify MCaE12A as a high affinity modulator of RyR2 and make it an important tool for RyR2 structure-to-function studies as well as for manipulating Ca 38 2+ homeostasis and 39 dynamic of cardiac cells.