The mechanism of LQTS related CaM mutation E141G interfering with Ca V 1.2 channels function through its C-lobe.

Autor: Zhang C; Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China., Shao D; Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China., Zheng X; Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China., Hao L; Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China. lyhao@cmu.edu.cn.
Jazyk: angličtina
Zdroj: Journal of physiology and biochemistry [J Physiol Biochem] 2024 Dec 19. Date of Electronic Publication: 2024 Dec 19.
DOI: 10.1007/s13105-024-01064-5
Abstrakt: Mutations in the CALM1-3 genes, which encode calmodulin (CaM), have been reported in clinical cases of long QT syndrome (LQTS). Specifically, the CaM mutant E141G (CaM E141G ) in the variant CALM1 gene has been identified as a causative factor in LQTS. This mutation disrupts the normal Ca 2+ -dependent inactivation (CDI) function of Ca V 1.2 channels. However, it is still unclear how CaM E141G interferes with the regulatory role of wild-type (WT) CaM on Ca V 1.2 channels and leads to abnormal CDI. A CaM molecule contains two lobes with similar structure, the N-lobe and the C-lobe. In this study, a CaM-truncated C-lobe mutant E141G (C-lobe E141G ) was engineered to exclude the impact of the unmutated N-lobe. Our findings revealed that at low Ca 2+ concentration ([Ca 2+ ]), the binding of C-lobe E141G to the preIQ, IQ and N-terminus (NT) of Ca V 1.2 channels has higher binding capacity (B max : 0.17, 0.22, 0.13) compared with those of WT C-lobe (B max : 0.04, 0.14, 0.11) in GST pull-down assay. With an increase in [Ca 2+ ], the Ca 2+ -dependency for C-lobe E141G binding to Ca V 1.2 channels was impaired. Moreover, C-lobe E141G induced the relative channel activity to 240.58 ± 51.37% at resting [Ca 2+ ], but it was unable to diminish the channel activity at high [Ca 2+ ] even in the presence of WT N-lobe, which may be responsible for the abnormal CDI of Ca V 1.2 channels affected by the LQTS-related CaM mutation. Our research provides preliminary insights into the mechanism by which the CaM mutation interferes with Ca V 1.2 channels function through its C-lobe.
Competing Interests: Declarations. Conflicts of interest: The authors declare no competing interests.
(© 2024. The Author(s) under exclusive licence to University of Navarra.)
Databáze: MEDLINE
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