Stretching the limits of antiarrhythmic drug therapy: The promise of small-conductance calcium-activated potassium channel blockers

Heijman, Jordi; Rahm, Ann‐Kathrin; Dobrev, Dobromir

doi:10.1016/j.ijcha.2021.100924

Cited by 2 publications

(2 citation statements)

References 24 publications

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“…Among the ion channels, potassium channels have the most subtypes and the most complex functions and are the focus of much clinical and scientific research. For example, research has been conducted on voltage-gated potassium channels, such as Kv1, Kv2, Kv3, and Kv4 (Heijman et al, 2021 ; Ikeno et al, 2021 ; Kleis et al, 2022 ). The Kv family of potassium channels are glycosylated polypeptide complexes composed of four α-subunits and four β-auxiliaries.…”

Section: Introductionmentioning

confidence: 99%

Rare KCND3 Loss-of-Function Mutation Associated With the SCA19/22

Liu

Hao

et al. 2022

Front. Mol. Neurosci.

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Spinocerebellar ataxia 19/22 (SCA19/22) is a rare neurodegenerative disorder caused by mutations of the KCND3 gene, which encodes the Kv4. 3 protein. Currently, only 22 KCND3 single-nucleotide mutation sites of SCA19/22 have been reported worldwide, and detailed pathogenesis remains unclear. In this study, Sanger sequencing was used to screen 115 probands of cerebellar ataxia families in 67 patients with sporadic cerebellar ataxia and 200 healthy people to identify KCND3 mutations. Mutant gene products showed pathogenicity damage, and the polarity was changed. Next, we established induced pluripotent stem cells (iPSCs) derived from SCA19/22 patients. Using a transcriptome sequencing technique, we found that protein processing in the endoplasmic reticulum was significantly enriched in SCA19/22-iPS-derived neurons and was closely related to endoplasmic reticulum stress (ERS) and apoptosis. In addition, Western blotting of the SCA19/22-iPS-derived neurons showed a reduction in Kv4.3; but, activation of transcription factor 4 (ATF4) and C/EBP homologous protein was increased. Therefore, the c.1130 C>T (p.T377M) mutation of the KCND3 gene may mediate misfold and aggregation of Kv4.3, which activates the ERS and further induces neuron apoptosis involved in SCA19/22.

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Section: Introductionmentioning

confidence: 99%

Rare KCND3 Loss-of-Function Mutation Associated With the SCA19/22

Liu

Hao

et al. 2022

Front. Mol. Neurosci.

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“…Although expressed in both atrial and ventricular tissue, under normal physiological conditions SK channels play a role in atrial, but not ventricular repolarization [ 37 , 38 ]. Numerous preclinical studies have demonstrated clear antiarrhythmic effects of SK-channel inhibition on the termination of AF as well as prevention of arrhythmia reinduction due to prolongation of the action potential duration and the effective refractory period [ 39 – 45 ], even in the presence of relatively advanced forms of AF that were refractory to cardioversion by currently approved and rather effective AADs [ 43 ]. Recent work demonstrated that SK current is up-regulated in patients with persistent AF due to a functional up-regulation resulting from phosphatase-2A-dependent calmodulin-Thr80 dephosphorylation and enhanced SK-channel trafficking to the sarcolemma.…”

Section: Recent Advances In Aad Therapiesmentioning

confidence: 99%

Recent Advances in Antiarrhythmic Drug Therapy

Saljic

Heijman

Dobrev

2023

Drugs

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Cardiac arrhythmias remain a common cause of death and disability. Antiarrhythmic drugs (AADs) and antiarrhythmic agents remain a cornerstone of current cardiac arrhythmia management, despite moderate efficacy and the potential for significant adverse proarrhythmic effects. Due to conceptual, regulatory and financial considerations, the number of novel antiarrhythmic targets and agents in the development pipeline has decreased substantially during the last few decades. However, several promising candidates remain and there are exciting developments in repurposing and reformulating already existing drugs for indications related to cardiac arrhythmias. This review discusses the key conceptual considerations for the development of new antiarrhythmic agents, summarizes new compounds and formulations currently in clinical development for rhythm control of atrial fibrillation, and highlights the potential for drug repurposing. Finally, future directions in AAD development are discussed. Together with an ever-increasing understanding of the molecular mechanisms underlying cardiac arrhythmias, these components support a cautiously optimistic outlook towards improved pharmacological treatment opportunities for patients suffering from cardiac arrhythmias.

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Stretching the limits of antiarrhythmic drug therapy: The promise of small-conductance calcium-activated potassium channel blockers

Cited by 2 publications

References 24 publications

Rare KCND3 Loss-of-Function Mutation Associated With the SCA19/22

Rare KCND3 Loss-of-Function Mutation Associated With the SCA19/22

Recent Advances in Antiarrhythmic Drug Therapy

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