Atrial Fibrillation: Focus on Myocardial Connexins and Gap Junctions

Abstract

Atrial fibrillation (AF) represents the most common type of clinical cardiac arrhythmia worldwide and contributes to substantial morbidity, mortality and socioeconomic burden. Aggregating evidence highlights the strong genetic basis of AF. In addition to chromosomal abnormalities, pathogenic mutations in over 50 genes have been causally linked to AF, of which the majority encode ion channels, cardiac structural proteins, transcription factors and gap junction channels. In the heart, gap junctions comprised of connexins (Cxs) form intercellular pathways responsible for electrical coupling and rapid coordinated action potential propagation between adjacent cardiomyocytes. Among the 21 isoforms of connexins already identified in the mammal genomes, 5 isoforms (Cx37, Cx40, Cx43, Cx45 and Cx46) are expressed in human heart. Abnormal electrical coupling between cardiomyocytes caused by structural remodeling of gap junction channels (alterations in connexin distribution and protein levels) has been associated with enhanced susceptibility to AF and recent studies have revealed multiple causative mutations or polymorphisms in 4 isoforms of connexins predisposing to AF. In this review, an overview of the genetics of AF is made, with a focus on the roles of mutant myocardial connexins and gap junctions in the pathogenesis of AF, to underscore the hypothesis that cardiac connexins are a major molecular target in the management of AF.

Arrhythmic Effects Evaluated on Caenorhabditis elegans: The Case of Polypyrrole Nanoparticles

“…In order to understand the possible molecular mechanism of action of Ppy NPs, we employed two mutant strains with slow pumping rates. The JD21 strain has a deletion mutation in cca-1 , a voltage-gated calcium channel homologous to human low-voltage T-type calcium channels CACNA1G , CACNA1H , and CACNA1I (Cav3 genes), with mutations implicated in long QT syndrome (LQT9). , On the other hand, the additional strain used, DA464, has a mutation in the eat-5 innexin gap junction, which shares structural and functional similarities with human connexin gap junctions, mutations of which are associated with atrial fibrillation . The response of JD21 and DA464 to commercially available cardiac drugs, PL and RE, followed the expected results (Figure S5).…”

Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

“…In mammals, the connexin gene family consists of 21 members, which are categorized 5 groups, and their proteins are named after their molecular mass, which vary between 23 and 62 kDa (Cx23-Cx62) [ 76 , 77 ]. In the human heart, three isoforms of connexins, including Cx45, Cx40, and Cx43, are highly expressed, with each isotype characterized by a specific spatiotemporal expression pattern and a distinct permeation property [ 82 ]. During embryogenesis, Cx45 is the first connexin to be expressed in the heart, while in the hearts of adults, abundant expression of Cx45 is restricted to the auricles as well as the conduction tissue, encompassing the sinoatrial nodes and atrioventricular nodes as well as the His-Purkinje fibers, with less expression of Cx45 in both atria and ventricles [ 83 ].…”

Connexin hemichannels as candidate targets for cardioprotective and anti-arrhythmic treatments

“…Atrial cardiomyocytes express both Cx40 and Cx43, with Cx40 showing the largest expression. Several mutations as well as a rare polymorphism have been reported in the Cx40 GJA5 gene in human atrial fibrillation (AF) patients (120,121), but little or nothing is known about their functional impact on Cx40-based HCs. As this Review focuses on Cx43 HCs, we include in the discussion below a recent report of Cx43 HC involvement in AF associated with a rare human mutation in the MYL4 gene (c.234delC) as a heritable cause of AF (122).…”