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Gap Junctions and Connexins in Health and Disease - Volume II

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Special Issue Information

Dear Colleagues,

Connexins are pore-forming proteins incorporated in the cellular membrane, where they coalesce into hexamer connexons (hemichannels). They either serve as an interface between the intracellular molecular milieu and the extracellular environment or pair up with other connexons embedded in the membrane of a neighbor cell to form intercellular passageways. The latter structure is called the gap junction and allows for the transcellular movement of ions and small-weight molecules. Both hemichannels and gap junctions can serve metabolic and/or electrical communication purposes for various cells in the body; thus, they appear to be essential and versatile factors in conducting many specific functions for living systems. Nevertheless, disruption or exacerbation of hemichannel and gap junction functioning are related to a number of pathological conditions, further demonstrating their essential roles in the life of living cells. Finally, gap junctions have also been proposed to distribute apoptotic factors (death signals) between connected cells. This so-called bystander effect underlies a secondary loss of cells that maintain gap junction contact with their injured neighbors even if they escape a primary harmful insult. Due to the latter feature, gap junctions have recently been identified as potential therapeutic targets in trials using pharmacological blockade, gene therapy, or electrical stimulation. This Special Issue intends to bring work from many different fields of biology together to reveal recent advances in both discovery and clinical research, with a focus on connexins and gap junctions.

Prof. Dr. Béla Völgyi
Dr. Tamas Kovacs-Oller
Guest Editors

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Published Papers (1 paper)

Research

19 pages, 7677 KiB

Open AccessArticle

Casein Kinase 1 Phosphomimetic Mutations Negatively Impact Connexin-43 Gap Junctions in Human Pluripotent Stem Cell-Derived Cardiomyocytes

by Rasha Al-attar, Joseph Jargstorf, Rocco Romagnuolo, Mariam Jouni, Faisal J. Alibhai, Paul D. Lampe, Joell L. Solan and Michael A. Laflamme

Biomolecules 2024, 14(1), 61; https://doi.org/10.3390/biom14010061 - 2 Jan 2024

Viewed by 1522

Abstract

The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has shown promise in preclinical models of myocardial infarction, but graft myocardium exhibits incomplete host–graft electromechanical integration and a propensity for pro-arrhythmic behavior. Perhaps contributing to this situation, hPSC-CM grafts show low expression of connexin 43 (Cx43), the major gap junction (GJ) protein, in ventricular myocardia. We hypothesized that Cx43 expression and function could be rescued by engineering Cx43 in hPSC-CMs with a series of phosphatase-resistant mutations at three casein kinase 1 phosphorylation sites (Cx43-S3E) that have been previously reported to stabilize Cx43 GJs and reduce arrhythmias in transgenic mice. However, contrary to our predictions, transgenic Cx43-S3E hPSC-CMs exhibited reduced Cx43 expression relative to wild-type cells, both at baseline and following ischemic challenge. Cx43-S3E hPSC-CMs showed correspondingly slower conduction velocities, increased automaticity, and differential expression of other connexin isoforms and various genes involved in cardiac excitation–contraction coupling. Cx43-S3E hPSC-CMs also had phosphorylation marks associated with Cx43 GJ internalization, a finding that may account for their impaired GJ localization. Taken collectively, our data indicate that the Cx43-S3E mutation behaves differently in hPSC-CMs than in adult mouse ventricular myocytes and that multiple biological factors likely need to be addressed synchronously to ensure proper Cx43 expression, localization, and function. Full article

(This article belongs to the Special Issue Gap Junctions and Connexins in Health and Disease - Volume II)

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