ArticleJournal of molecular and cellular cardiology2014
Degradation of a connexin40 mutant linked to atrial fibrillation is accelerated.
Article in Journal of molecular and cellular cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- The effects of polyunsaturated fatty acids and antioxidant vitamins on atrial oxidative stress, nitrotyrosine residues, and connexins following extracorporeal circulation in patients undergoing cardiac surgery.Molecular and cellular biochemistry · 2017Trial
- NovelBiomedicines · 2026Article
- Discovery ofBiology · 2023Article
- The roles of connexins and gap junctions in the progression of cancer.Cell communication and signaling : CCS · 2023Review
- Review
- Interrogation of Carboxy-Terminus LocalizedInternational journal of molecular sciences · 2022Article
- Cardiac Pressure Overload Decreases ETV1 Expression in the Left Atrium, Contributing to Atrial Electrical and Structural Remodeling.Circulation · 2021Article
- Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications.Cellular and molecular life sciences : CMLS · 2020Review
- Phosphorylation regulates connexin43/ZO-1 binding and release, an important step in gap junction turnover.Molecular biology of the cell · 2017Article
- Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications.Pharmacological reviews · 2017Review
- Regulation of cardiac gap junctions by protein phosphatases.Journal of molecular and cellular cardiology · 2017Review
- Molecular mechanisms regulating formation, trafficking and processing of annular gap junctions.BMC cell biology · 2016Review
- Degradation of gap junction connexins is regulated by the interaction with Cx43-interacting protein of 75 kDa (CIP75).The Biochemical journal · 2015Article
- Connexin40 abnormalities and atrial fibrillation in the human heart.Journal of molecular and cellular cardiology · 2014Article
- Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Several Cx40 mutants have been identified in patients with atrial fibrillation (AF). We have been working to identify physiological or cell biological abnormalities of several of these human mutants that might explain how they contribute to disease pathogenesis. Wild type (wt) Cx40 or four different mutants (P88S, G38D, V85I, and L229M) were expressed by the transfection of communication-deficient HeLa cells or HL-1 cardiomyocytes. Biophysical channel properties and the sub-cellular localization and protein levels of Cx40 were characterized. Wild type Cx40 and all mutants except P88S formed gap junction plaques and induced significant gap junctional conductances. The functional mutants showed only modest alterations of single channel conductances or gating by trans-junctional voltage as compared to wtCx40. However, immunoblotting indicated that the steady state levels of G38D, V85I, and L229M were reduced relative to wtCx40; most strikingly, G38D was only 20-31% of wild type levels. After the inhibition of protein synthesis with cycloheximide, G38D (and to a lesser extent the other mutants) disappeared much faster than wtCx40. Treatment with the proteasomal inhibitor, epoxomicin, greatly increased levels of G38D and restored the abundance of gap junctions and the extent of intercellular dye transfer. Thus, G38D, V85I, and L229M are functional mutants of Cx40 with small alterations of physiological properties, but accelerated degradation by the proteasome. These findings suggest a novel mechanism (protein instability) for the pathogenesis of AF due to a connexin mutation and a novel approach to therapy (protease inhibition).
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Registered trials
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