Last update 01 Nov 2024

CaM x Nav1.5

Last update 01 Nov 2024

Basic Info

Related Targets

CaMNav1.5

Drugs associated with CaM x Nav1.5

Aprindine Hydrochloride

Target

CaM x Nav1.5

Mechanism

CaM antagonists [+1]

Active Org.

Bayer Yakuhin Ltd. [+2]

Originator Org.

Tianjin Pharm Research Inst Pharm Co Ltd.

Active Indication

Tachycardia [+1]

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date01 Jan 1981

100 Clinical Results associated with CaM x Nav1.5

100 Translational Medicine associated with CaM x Nav1.5

0 Patents (Medical) associated with CaM x Nav1.5

Literatures (Medical) associated with CaM x Nav1.5

01 Aug 2024·Journal of Cellular Biochemistry

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

Article

Author: Nounesis, George ; Kontogianni, Iris ; Nasrallah, Gheyath K ; Lai, F Anthony ; Nomikos, Michail ; Safieh-Garabedian, Bared ; Da'as, Sahar I ; Calver, Brian L ; Saleh, Alaaeldin ; Abdelrahman, Doua ; Thanassoulas, Angelos ; Hasan, Waseem

AbstractCalmodulin (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.

01 Mar 2023·Genetics in Medicine

Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies

Article

Author: O'Neill, Matthew J ; Denjoy, Isabelle ; Sala, Luca ; Spazzolini, Carla ; Kozek, Krystian ; Leenhardt, Antoine ; Kashiwa, Asami ; Extramiana, Fabrice ; Horie, Minoru ; Roden, Dan M ; Tao, Ran ; Crotti, Lia ; Kotta, Maria-Christina ; Dagradi, Federica ; Wada, Yuko ; Ohno, Seiko ; Kroncke, Brett M ; Schwartz, Peter J ; Salem, Joe-Elie

PURPOSEThe congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.METHODSWe generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure.RESULTSBayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.CONCLUSIONSBayesian penetrance estimates provide a continuous framework for variant interpretation.

01 Feb 2023·Biophysical Journal

Calmodulin binds FGF12A to regulate Nav1.5 channel inactivation

Article

Author: Marras, Martina ; Abella, Carlota ; Angsutararux, Paweorn ; Woodbury, Lucy S ; Silva, Jonathan R

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