Long QT syndrome‐associated calmodulin variants disrupt the activity of the slowly activating delayed rectifier potassium channel

McCormick, Liam F.; Wadmore, Kirsty; Milburn, Amy; Gupta, Nitika; Morris, Rachael; Held, Marie; Prakash, O.; Carr, James; Barrett‐Jolley, Richard; Helassa, Nordine; Trayanova, Natalia A.

doi:10.1113/jp284994

Cited by 3 publications

(1 citation statement)

References 99 publications

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“…In contrast, a hyperpolarizing V 1/2 shift occurs when the pore is propped open by an increasing number of L353K mutations in the channel complex ( Meisel et al, 2012 ), where presumably CaM molecules bound to mutated subunits are already out of the way of those remaining subunits that are starting from a closed pore configuration. Not surprisingly, several mutations in CaM linked to long QT-interval syndrome are also known to shift the V 1/2 of I Ks to more positive potentials ( McCormick et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors

Fedida,

Sastre,

Dou

et al. 2024

Journal of General Physiology

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The ion-conducting IKs channel complex, important in cardiac repolarization and arrhythmias, comprises tetramers of KCNQ1 α-subunits along with 1–4 KCNE1 accessory subunits and calmodulin regulatory molecules. The E160R mutation in individual KCNQ1 subunits was used to prevent activation of voltage sensors and allow direct determination of transition rate data from complexes opening with a fixed number of 1, 2, or 4 activatable voltage sensors. Markov models were used to test the suitability of sequential versus allosteric models of IKs activation by comparing simulations with experimental steady-state and transient activation kinetics, voltage-sensor fluorescence from channels with two or four activatable domains, and limiting slope currents at negative potentials. Sequential Hodgkin–Huxley-type models approximately describe IKs currents but cannot explain an activation delay in channels with only one activatable subunit or the hyperpolarizing shift in the conductance–voltage relationship with more activatable voltage sensors. Incorporating two voltage sensor activation steps in sequential models and a concerted step in opening via rates derived from fluorescence measurements improves models but does not resolve fundamental differences with experimental data. Limiting slope current data that show the opening of channels at negative potentials and very low open probability are better simulated using allosteric models of activation with one transition per voltage sensor, which implies that movement of all four sensors is not required for IKs conductance. Tiered allosteric models with two activating transitions per voltage sensor can fully account for IKs current and fluorescence activation kinetics in constructs with different numbers of activatable voltage sensors.

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Section: Discussionmentioning

confidence: 99%

Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors

Fedida,

Sastre,

Dou

et al. 2024

Journal of General Physiology

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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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Calmodulin mutations can underlie the phenotype of long QT syndrome variant 1

Kass

2023

The Journal of Physiology

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Long QT syndrome‐associated calmodulin variants disrupt the activity of the slowly activating delayed rectifier potassium channel

Cited by 3 publications

References 99 publications

Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors

Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors

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

Calmodulin mutations can underlie the phenotype of long QT syndrome variant 1

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