Key result
The CaM-E141G mutant attenuated the Ca2+-dependent decrease in CaV1.2 channel activity compared to wild-type (55.99% vs 24.88%) and induced a flickering gating mode.
Why the study?
Calmodulin mutations are associated with congenital LQTS, but the interaction of the critical CaM-E141G missense variant with the CaV1.2 channel had not been determined.
Absolute Event Rate: 55.99% vs 24.88%
The CaM-E141G mutation disrupts binding with the CaV1.2 channel and induces a flickering gating mode, providing a mechanistic basis for its association with long QT syndrome.
Supports CaM-E141G mechanisms in long QT syndrome; leaves open human translation and therapeutic relevance.
Calmodulin (CaM) mutations are associated with congenital long QT (LQT) syndrome (LQTS), which may be related to the dysregulation of the cardiac-predominant Ca 2+ channel isoform Ca V 1.2. Among various mutants, CaM-E141G was identified as a critical missense variant. However, the interaction of this CaM mutant with the Ca V 1.2 channel has not been determined. In this study, by utilizing a semiquantitative pull-down assay, we explored the interaction of CaM-E141G with CaM-binding peptide fragments of the Ca V 1.2 channel. Using the patch-clamp technique, we also investigated the electrophysiological effects of the mutant on Ca V 1.2 channel activity. We found that the maximum binding (B max ) of CaM-E141G to the proximal COOH-terminal region, PreIQ-IQ, PreIQ, IQ, and NT (an NH 2 -terminal peptide) was decreased (by 17.71–59.26%) compared with that of wild-type CaM (CaM-WT). In particular, the Ca 2+ -dependent increase in B max became slower with the combination of CaM-E141G + PreIQ and IQ but faster in the case of NT. Functionally, CaM-WT and CaM-E141G at 500 nM Ca 2+ decreased Ca V 1.2 channel activity to 24.88% and 55.99%, respectively, compared with 100 nM Ca 2+ , showing that the inhibitory effect was attenuated in CaM-E141G. The mean open time of the Ca V 1.2 channel was increased, and the number of blank traces with no channel opening was significantly decreased. Overall, CaM-E141G exhibits disrupted binding with the Ca V 1.2 channel and induces a flickering gating mode, which may result in the dysfunction of the Ca V 1.2 channel and, thus, the development of LQTS. The present study is the first to investigate the detailed binding properties and single-channel gating mode induced by the interaction of CaM-E141G with the Ca V 1.2 channel.
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Su et al. (2020) studied Long QT syndrome (LQTS). CaM-E141G mutant vs. Wild-type CaM (CaM-WT) was evaluated on CaV1.2 channel activity at 500 nM Ca2+ compared with 100 nM Ca2+. The CaM-E141G mutant attenuated the Ca2+-dependent decrease in CaV1.2 channel activity compared to wild-type (55.99% vs 24.88%) and induced a flickering gating mode.
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