Calmodulin Mutations in Human Disease

Hussey, John W.; Limpitikul, Worawan B.; Dick, Ivy E.

doi:10.1080/19336950.2023.2165278

Cited by 16 publications

(27 citation statements)

References 115 publications

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“…Missense variants in CaM have emerged in recent years to underlie severe arrhythmia with high mortality rate 14,[16][17][18][19][20] . As CaM targets numerous ion channels important to the cardiac action potential, the mechanisms of CaM-induced arrhythmia ("calmodulinopathy") are necessarily complex.…”

Section: Discussionmentioning

confidence: 99%

“…As CaM targets numerous ion channels important to the cardiac action potential, the mechanisms of CaM-induced arrhythmia ("calmodulinopathy") are necessarily complex. Multiple studies have shown that CaM variants can significantly impact CaV1.2 and/or RyR2 function 14,[16][17][18]23,26,27,29,30,[32][33][34]57 . By contrast, although CaM also associates and regulates KCNQ1 channel membrane trafficking and function, relatively little is known regarding whether KCNQ1 or IKs dysfunction may also contribute to calmodulinopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive studies have established that several CaM missense variants impair Ca 2+ binding 16,[21][22][23][24][25][26][27][28] . To date, CaM variants are most extensively evaluated as related to CaV1.2 or RyR2, with many variants shown to induce CaV1.2 and RyR2 dysfunction thereby contributing to arrhythmogenesis 14,22,27,[29][30][31][32][33][34] . By comparison, relatively little is known regarding whether CaM variants may also alter KCNQ1 channel function and membrane expression, with only a few studies suggesting potential effects 10,28,35 .…”

Section: Introductionmentioning

confidence: 99%

“…Independent of Ca 2+ -sensing function, CaM binding also modulates baseline channel function in CaV1.2, NaV1.5, and KCNQ1 [8][9][10][11] . Inherited or de novo mutations in these channels causing CaM dysregulation are associated with arrhythmias such as Timothy syndrome (TS), Brugada syndrome (BrS), and long QT syndrome (LQTS) 9,[12][13][14] . Three genes in the human genome (CALM1-3) encode for CaM with 100% conservation in amino acid identity 3,15 , and CaM was long-thought to be intolerant of primary sequence alterations.…”

Section: Introductionmentioning

confidence: 99%

“…Three genes in the human genome (CALM1-3) encode for CaM with 100% conservation in amino acid identity 3,15 , and CaM was long-thought to be intolerant of primary sequence alterations. Recently, human missense variants in CaM have emerged as a molecular factor underlying arrhythmias ("calmodulinopathy") such as LQTS and catecholaminergic polymorphic ventricular tachycardia (CPVT) associated with high mortality rate 14,[16][17][18][19][20] . As CaM variants cause dysfunction in many combinations of their regulatory targets, calmodulinopathy mechanisms are fundamentally complex.…”

Section: Introductionmentioning

confidence: 99%

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Arrhythmia-associated Calmodulin Variants Interact with KCNQ1 to Confer Aberrant Membrane Trafficking and Function

Kang

Woodbury

Angsutararux

et al. 2023

Preprint

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Rationale: Missense variants in calmodulin (CaM) predispose patients to arrhythmias associated with high mortality rates. As CaM regulates several key cardiac ion channels, a mechanistic understanding of CaM variant-associated arrhythmias requires elucidating individual CaM variant effect on distinct channels. One key CaM regulatory target is the KCNQ1 (KV7.1) voltage-gated potassium channel that underlie the IKs current. Yet, relatively little is known as to how CaM variants interact with KCNQ1 or affect its function. Objective: To observe how arrhythmia-associated CaM variants affect binding to KCNQ1, channel membrane trafficking, and KCNQ1 function. Methods and Results: We combine a live-cell FRET binding assay, fluorescence trafficking assay, and functional electrophysiology to characterize >10 arrhythmia-associated CaM variants effect on KCNQ1. We identify one variant (G114W) that exhibits severely weakened binding to KCNQ1 but find that most other CaM variants interact with similar binding affinity to KCNQ1 when compared to CaM wild-type over physiological Ca2+ ranges. We further identify several CaM variants that affect KCNQ1 and IKs membrane trafficking and/or baseline current activation kinetics, thereby contextualizing KCNQ1 dysfunction in calmodulinopathy. Lastly, we delineate CaM variants with no effect on KCNQ1 function. Conclusions: This study provides comprehensive functional data that reveal how CaM variants contribute to creating a pro-arrhythmic substrate by causing abnormal KCNQ1 membrane trafficking and current conduction. We find that CaM variant regulation of KCNQ1 is not uniform with effects varying from benign to significant loss of function. This study provides a new approach to collecting details of CaM binding that are key for understanding how CaM variants predispose patients to arrhythmia via the dysregulation of multiple cardiac ion channels.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Arrhythmia-associated Calmodulin Variants Interact with KCNQ1 to Confer Aberrant Membrane Trafficking and Function

Kang

Woodbury

Angsutararux

et al. 2023

Preprint

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Divergent Biochemical Properties and Disparate Impact of Arrhythmogenic Calmodulin Mutations on Zebrafish Cardiac Function

Da'as,

Thanassoulas,

Calver

et al. 2024

J of Cellular Biochemistry

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Calmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca2+)‐binding sensor that plays a vital role in many cellular processes by binding and regulating the activity of over 300 protein targets. In cardiac muscle, CaM modulates directly or indirectly the activity of several proteins that play a key role in excitation‐contraction coupling (ECC), such as ryanodine receptor type 2 (RyR2), l‐type Ca2+ (Cav1.2), sodium (NaV1.5) and potassium (KV7.1) channels. Many recent clinical and genetic studies have reported a series of CaM mutations in patients with life‐threatening arrhythmogenic syndromes, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently showed that four arrhythmogenic CaM mutations (N98I, D132E, D134H, and Q136P) significantly reduce the binding of CaM to RyR2. Herein, we investigate in vivo functional effects of these CaM mutations on the normal zebrafish embryonic heart function by microinjecting complementary RNA corresponding to CaMN98I, CaMD132E, CaMD134H, and CaMQ136P mutants. Expression of CaMD132E and CaMD134H mutants results in significant reduction of the zebrafish heart rate, mimicking a severe form of human bradycardia, whereas expression of CaMQ136P results in an increased heart rate mimicking human ventricular tachycardia. Moreover, analysis of cardiac ventricular rhythm revealed that the CaMD132E and CaMN98I zebrafish groups display an irregular pattern of heart beating and increased amplitude in comparison to the control groups. Furthermore, circular dichroism spectroscopy experiments using recombinant CaM proteins reveals a decreased structural stability of the four mutants compared to the wild‐type CaM protein in the presence of Ca2+. Finally, Ca2+‐binding studies indicates that all CaM mutations display reduced CaM Ca2+‐binding affinities, with CaMD132E exhibiting the most prominent change. Our data suggest that CaM mutations can trigger different arrhythmogenic phenotypes through multiple and complex molecular mechanisms.

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Energetic and structural insights behind calcium induced conformational transition in calmodulin

Halder,

Warshel

2023

Proteins

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Calmodulin (CaM) is a key signaling protein that triggers several cellular and physiological processes inside the cell. Upon binding with calcium ion, CaM undergoes large scale conformational transition from a closed state to an open state that facilitates its interaction with various target protein and regulates their activity. This work explores the origin of the energetic and structural variation of the wild type and mutated CaM and explores the molecular origin for the structural differences between them. We first calculated the sequential calcium binding energy to CaM using the PDLD/S‐LRA/β approach. This study shows a very good correlation with experimental calcium binding energies. Next we calculated the calcium binding energies to the wild type CaM and several mutated CaM systems which were reported experimentally. On the structural aspect, it has been reported experimentally that certain mutation (Q41L‐K75I) in calcium bound CaM leads to complete conformational transition from an open to a closed state. By using equilibrium molecular dynamics simulation, free energy calculation and contact frequency map analysis, we have shown that the formation of a cluster of long‐range hydrophobic contacts, initiated by the Q41L‐K75I CaM variant is the driving force behind its closing motion. This study unravels the energetics and structural aspects behind calcium ion induced conformational changes in wild type CaM and its variant.

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Calmodulin Mutations in Human Disease

Cited by 16 publications

References 115 publications

Arrhythmia-associated Calmodulin Variants Interact with KCNQ1 to Confer Aberrant Membrane Trafficking and Function

Arrhythmia-associated Calmodulin Variants Interact with KCNQ1 to Confer Aberrant Membrane Trafficking and Function

Divergent Biochemical Properties and Disparate Impact of Arrhythmogenic Calmodulin Mutations on Zebrafish Cardiac Function

Energetic and structural insights behind calcium induced conformational transition in calmodulin

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