Atrial Fibrillation-Linked Germline GJA5/Connexin40 Mutants Showed an Increased Hemichannel Function

Sun, Yiguo; Hills, Matthew D.; Ye, Willy G.; Tong, Xiaoling; Bai, Donglin

doi:10.1371/journal.pone.0095125

Cited by 20 publications

(27 citation statements)

References 36 publications

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“…In contrast, the expression of V85I, L221I or L229M in N2A cell pairs did not show any reduction of the G j , indicating an apparently normal GJ coupling of these mutants. Further investigations revealed that L229M, but not V85I and L221I, displayed a transdominant negative action on the G j of co‐expressed Cx43 [100,102]. These studies indicate that many of the AF‐linked Cx40 mutants showed impairment of GJ channels via different mechanisms (Table 1 ), which may play a role in promoting atrial arrhythmias leading to AF.…”

Section: Atrial Fibrillation‐linked Connexin Mutations and Mutant/knomentioning

confidence: 88%

“…Interestingly that Q49X also reduced the localization of wild‐type Cx40 and Cx43 to the cell–cell interfaces and their G j [101]. In contrast to Q49X, all other AF‐linked germline mutants (I75F, V85I, A96S, L221I and L229M) did not show any major defects in the localization and formation of GJ plaques at the cell–cell interfaces [96,100,102]. However, dual patch clamp studies indicated that both I75F and A96S virtually eliminated G j in cell pairs expressing these mutants [96,100].…”

Section: Atrial Fibrillation‐linked Connexin Mutations and Mutant/knomentioning

confidence: 99%

“…As discussed earlier that undocked hemichannels can exist on the cell plasma membrane and may play a role in the pathogenesis of several disease‐linked connexin mutations. To test hemichannel function of the AF‐linked germline Cx40 mutants, especially those without any detectable changes in GJ function (V85I and L221I), propidium iodide (PI)‐uptake assay under divalent cation free condition was used [102]. Interestingly, expressing either V85I or L221I in HeLa cells showed a prominent PI‐uptake while Cx40 and other AF‐linked germline Cx40 mutants failed to display PI‐uptake, indicating an enhanced hemichannel function of these two AF‐linked mutants [102] (Table 1).…”

Section: Atrial Fibrillation‐linked Connexin Mutations and Mutant/knomentioning

confidence: 99%

“…To test hemichannel function of the AF‐linked germline Cx40 mutants, especially those without any detectable changes in GJ function (V85I and L221I), propidium iodide (PI)‐uptake assay under divalent cation free condition was used [102]. Interestingly, expressing either V85I or L221I in HeLa cells showed a prominent PI‐uptake while Cx40 and other AF‐linked germline Cx40 mutants failed to display PI‐uptake, indicating an enhanced hemichannel function of these two AF‐linked mutants [102] (Table 1). A gain‐of‐function in hemichannel activities of AF‐linked Cx40 mutants revealed a novel possible mechanism for the AF pathogenesis.…”

Section: Atrial Fibrillation‐linked Connexin Mutations and Mutant/knomentioning

confidence: 99%

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Atrial fibrillation‐linked GJA5/connexin40 mutants impaired gap junctions via different mechanisms

Bai

2014

FEBS Letters

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a b s t r a c tThe gap junctions (GJs) formed by Cx40 and Cx43 provide a low resistance passage allowing for rapid propagation of action potentials. Sporadic somatic mutations in GJA5 (encoding Cx40) have been identified in lone atrial fibrillation (AF) patients. More recently germline autosomal dominantly inherited mutations in GJA5 have been found in early onset lone AF patients in several families over generations. Characterizations of these AF-linked Cx40 mutants in model cells and in patient tissues revealed that some of the mutants reduced GJ channel function due to an impaired trafficking or channel formation. While others showed a gain-of-function in hemichannels. These functional alterations in GJs or hemichannel may play an important role in the pathogenesis of AF in the mutant carriers.

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Section: Atrial Fibrillation‐linked Connexin Mutations and Mutant/knomentioning

confidence: 88%

Section: Atrial Fibrillation‐linked Connexin Mutations and Mutant/knomentioning

confidence: 99%

Section: Atrial Fibrillation‐linked Connexin Mutations and Mutant/knomentioning

confidence: 99%

Section: Atrial Fibrillation‐linked Connexin Mutations and Mutant/knomentioning

confidence: 99%

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Atrial fibrillation‐linked GJA5/connexin40 mutants impaired gap junctions via different mechanisms

Bai

2014

FEBS Letters

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“…Several SNPs of the gene encoding Cx40 lead to abnormal connexin localization and impaired gap junction channels (Sun et al, 2014). This aberration may result in the development of AF.…”

Section: Introductionmentioning

confidence: 99%

Association between -44G/A and +71A/G polymorphisms in the connexin 40 gene and atrial fibrillation in Uyghur and Han populations in Xinjiang, China

Hailati¹,

Yang²,

Zhang³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. We aimed to elucidate the association between connexin 40 (Cx40) genetic polymorphisms and atrial fibrillation (AF) in a Chinese population in Xinjiang comprising Uyghur and Han individuals. We enrolled 275 Uyghur and 305 age-and gendermatched Han subjects, and used polymerase chain reaction to detect single nucleotide polymorphisms (SNPs; -44G/A and +71A/G) in the gene encoding Cx40. A mutation screening was performed by direct sequencing and calculation of genotype and allele frequencies among AF patients and control subjects to determine the relationship between these variants and this condition in Uyghur and Han populations. The two SNPs examined were significantly associated with AF in both ethnic groups. Further analysis showed the SNPs to be in perfect linkage disequilibrium in both AF and control groups among Uyghur and Han individuals. In both populations -44AA genotype and A allele frequencies among AF patients were significantly higher than those in the control group. In addition, under the dominant model (GG vs GA+AA), a significant difference in the distribution of Cx40 -44G/ A genotypes was detected between patients and controls. Logistic regression analysis revealed that Cx40 genetic polymorphisms increase AF risk in Uyghur and Han residents of Xinjiang. In conclusion, both the -44G/A and +71A/G variants of the gene encoding this protein are associated with AF in Uyghur and Han populations in northern China.

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A structural and functional comparison of gap junction channels composed of connexins and innexins

Skerrett

Williams

2016

Developmental Neurobiology

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Methods such as electron microscopy and electrophysiology led to the understanding that gap junctions were dense arrays of channels connecting the intracellular environments within almost all animal tissues. The characteristics of gap junctions were remarkably similar in preparations from phylogenetically diverse animals such as cnidarians and chordates. Although few studies directly compared them, minor differences were noted between gap junctions of vertebrates and invertebrates. For instance, a slightly wider gap was noted between cells of invertebrates and the spacing between invertebrate channels was generally greater. Connexins were identified as the structural component of vertebrate junctions in the 1980s and innexins as the structural component of pre‐chordate junctions in the 1990s. Despite a lack of similarity in gene sequence, connexins and innexins are remarkably similar. Innexins and connexins have the same membrane topology and form intercellular channels that play a variety of tissue‐ and temporally specific roles. Both protein types oligomerize to form large aqueous channels that allow the passage of ions and small metabolites and are regulated by factors such as pH, calcium, and voltage. Much more is currently known about the structure, function, and structure–function relationships of connexins. However, the innexin field is expanding. Greater knowledge of innexin channels will permit more detailed comparisons with their connexin‐based counterparts, and provide insight into the ubiquitous yet specific roles of gap junctions. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 522–547, 2017

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Atrial Fibrillation-Linked Germline GJA5/Connexin40 Mutants Showed an Increased Hemichannel Function

Cited by 20 publications

References 36 publications

Atrial fibrillation‐linked GJA5/connexin40 mutants impaired gap junctions via different mechanisms

Atrial fibrillation‐linked GJA5/connexin40 mutants impaired gap junctions via different mechanisms

Association between -44G/A and +71A/G polymorphisms in the connexin 40 gene and atrial fibrillation in Uyghur and Han populations in Xinjiang, China

A structural and functional comparison of gap junction channels composed of connexins and innexins

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