Prakash, Ohm, Held, Marie 
ORCID: 0000-0003-0118-5898, McCormick, Liam F ORCID: 0000-0001-9557-9403, Gupta, Nitika, Lian, Lu-Yun, Antonyuk, Svetlana, Haynes, Lee P ORCID: 0000-0002-1296-0338, Thomas, N Lowri and Helassa, Nordine
(2021)
CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms.
Journal of Cell Science.
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Abstract
<jats:p>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited condition that can cause fatal cardiac arrhythmia. Human mutations in the Ca2+ sensor calmodulin (CaM) have been associated with CPVT susceptibility, suggesting that CaM dysfunction is a key driver of the disease. However, the detailed molecular mechanism remains unclear. Focusing on the interaction with the cardiac ryanodine receptor (RyR2), we determined the effect of CPVT-associated variants N53I and A102V on the structural characteristics of CaM and on Ca2+ fluxes in live cells. We provide novel data showing that binding of both Ca2+/CaM-N53I and Ca2+/CaM-A102V to RyR23583-3603 is decreased. Ca2+/CaM:RyR23583-3603 high-resolution crystal structures highlight subtle conformational changes for the N53I variant, with A102V being similar to wild-type. We show that co-expression of CaM-N53I or CaM-A102V with RyR2 in HEK293 cells significantly increased the duration of Ca2+ events, CaM-A102V exhibited a lower frequency of Ca2+ oscillations. In addition, we show that CaMKIIδ phosphorylation activity is increased for A102V, compared to CaM-WT. This paper provides novel insight into the molecular mechanisms of CPVT-associated CaM variants and will facilitate development of strategies for future therapies.</jats:p>
| Item Type: | Article |
|---|---|
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences Faculty of Health and Life Sciences > Tech, Infrastructure and Environmental Directorate |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 11 Jan 2022 14:16 |
| Last Modified: | 18 Jan 2023 21:17 |
| DOI: | 10.1242/jcs.258796 |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3146212 |
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- CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms. (deposited 11 Jan 2022 14:16) [Currently Displayed]
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