CPVT-associated calmodulin variants N531 and A102V dysregulate Ca<SUP>2+</SUP> signalling via different mechanisms

Prakash, Ohm, Held, Marie ORCID: 0000-0003-0118-5898, McCormick, Liam F ORCID: 0000-0001-9557-9403, Gupta, Nitika ORCID: 0000-0003-3885-2500, Lian, Lu-Yun, Antonyuk, Svetlana ORCID: 0000-0002-2779-9946, Haynes, Lee P ORCID: 0000-0002-1296-0338, Thomas, N Lowri and Helassa, Nordine ORCID: 0000-0003-3743-1886 (2022) CPVT-associated calmodulin variants N531 and A102V dysregulate Ca<SUP>2+</SUP> signalling via different mechanisms. JOURNAL OF CELL SCIENCE, 135 (2). jcs258796-.

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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 interaction of both Ca2+/CaM-N53I and Ca2+/CaM-A102V with the RyR2 binding domain 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 (WT). 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 (also known as CAMK2D) 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 the development of strategies for future therapies.

Item Type:	Article
Uncontrolled Keywords:	CPVT, CaMKII, RyR2, Arrhythmia, Calcium signalling, Calmodulin
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 > Institute of Systems, Molecular and Integrative Biology Faculty of Health and Life Sciences > Tech, Infrastructure and Environmental Directorate
Depositing User:	Symplectic Admin
Date Deposited:	18 Jan 2022 16:49
Last Modified:	17 Oct 2023 22:35
DOI:	10.1242/jcs.258796
Open Access URL:	https://doi.org/10.1242/jcs.258796
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3147117

Available Versions of this Item

• CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms. (deposited 11 Jan 2022 14:16)
  • CPVT-associated calmodulin variants N531 and A102V dysregulate Ca<SUP>2+</SUP> signalling via different mechanisms. (deposited 18 Jan 2022 16:49) [Currently Displayed]