CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms

Prakash, Ohm, Held, Marie, McCormick, Liam F., Gupta, Nitika, Lian, Lu-Yun, Antonyuk, Svetlana, Haynes, Lee P., Thomas, N. Lowri ORCID: https://orcid.org/0000-0001-8822-8576 and Helassa, Nordine 2022. CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms. Journal of Cell Science 135 (2) , jcs258796. 10.1242/jcs.258796

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Additional Information:	This is an Open Access article distributed under the terms of the Creative Commons Attribution License
Publisher:	The Company of Biologists
ISSN:	0021-9533
Date of First Compliant Deposit:	10 January 2022
Date of Acceptance:	29 November 2021
Last Modified:	18 May 2023 12:52
URI:	https://orca.cardiff.ac.uk/id/eprint/146480

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