Mechanisms of Connexin Regulating Peptides

King, Dennis; Sedovy, Meghan W.; Leng, Xinyan; Xue, Jianxiang; Lamouille, Samy; Koval, Michael; Isakson, Brant E.; Johnstone, Scott R.

doi:10.3390/ijms221910186

Cited by 18 publications

(17 citation statements)

References 213 publications

(367 reference statements)

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“…Despite valuable insights into the structure and regulation of Cx HCs and GJCs [ 1 , 3 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], one may have the impression that matters arising from the lack of Cx subtype-specific inhibitors and pertinent structural issues stayed somewhat unexplored [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers

et al. 2021

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Connexin (Cx) proteins establish intercellular gap junction channels (Cx GJCs) through coupling of two apposed hexameric Cx hemichannels (Cx HCs, connexons). Pre- and post-GJ interfaces consist of extracellular EL1 and EL2 loops, each with three conserved cysteines. Previously, we reported that known peptide inhibitors, mimicking a variety of Cx43 sequences, appear non-selective when binding to homomeric Cx43 vs. Cx36 GJC homology model subtypes. In pursuit of finding potentially Cx subtype-specific inhibitors of connexon-connexon coupling, we aimed at to understand better how the GJ interface is formed. Here we report on the discovery of Cx GJC subtype-specific protein stabilization centers (SCs) featuring GJ interface architecture. First, the Cx43 GJC homology model, embedded in two opposed membrane bilayers, has been devised. Next, we endorsed the fluctuation dynamics of SCs of the interface domain of Cx43 GJC by applying standard molecular dynamics under open and closed cystine disulfide bond (CS-SC) preconditions. The simulations confirmed the major role of of the unique trans-GJ SC pattern comprising conserved (55N, 56T) and non-conserved (57Q) residues of the apposed EL1 loops in the stabilization of the GJC complex. Importantly, clusters of SC patterns residing close to the GJ interface domain appear to orient the interface formation via the numerous SCs between EL1 and EL2. These include central 54CS-S198C or 61CS-S192C contacts with residues 53R, 54C, 55N, 197D, 199F or 64V, 191P, respectively. In addition, we revealed that GJC interface formation is favoured when the psi dihedral angle of the nearby 193P residue is stable around 180° and the interface SCs disappear when this angle moves to the 0° to −45° range. The potential of the association of non-conserved residues with SC motifs in connexon-connexon coupling makes the development of Cx subtype-specific inhibitors viable.

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Section: Discussionmentioning

confidence: 99%

Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers

et al. 2021

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“…These efforts have resulted in an array of CxHC blockers, including connexin-specific mimetic peptides and anti-EL antibodies [ 16 , 20 ]. The utilizations of these CxHC blockers have helped frame our understanding of CxHC functions, even though the limitations and underlying mechanisms of these CxHC blockers are yet to be fully characterized [ 4 , 16 , 17 , 30 , 31 ].…”

Section: Selective Manipulation Of Cxhcmentioning

confidence: 99%

The Role of Connexin Hemichannels in Inflammatory Diseases

Peng

Wang

et al. 2022

Biology

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The connexin protein family consists of approximately 20 members, and is well recognized as the structural unit of the gap junction channels that perforate the plasma membranes of coupled cells and, thereby, mediate intercellular communication. Gap junctions are assembled by two preexisting hemichannels on the membranes of apposing cells. Non-junctional connexin hemichannels (CxHC) provide a conduit between the cell interior and the extracellular milieu, and are believed to be in a protectively closed state under physiological conditions. The development and characterization of the peptide mimetics of the amino acid sequences of connexins have resulted in the development of a panel of blockers with a higher selectivity for CxHC, which have become important tools for defining the role of CxHC in various biological processes. It is increasingly clear that CxHC can be induced to open by pathogen-associated molecular patterns. The opening of CxHC facilitates the release of damage-associated molecular patterns, a class of endogenous molecules that are critical for the pathogenesis of inflammatory diseases. The blockade of CxHC leads to attenuated inflammation, reduced tissue injury and improved organ function in human and animal models of about thirty inflammatory diseases and disorders. These findings demonstrate that CxHC may contribute to the intensification of inflammation, and serve as a common target in the treatments of various inflammatory diseases. In this review, we provide an update on the progress in the understanding of CxHC, with a focus on the role of these channels in inflammatory diseases.

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“…New concepts of using Cx43 as a tool to develop the specific liposomes that need to be delivered to the Cx43 expression cells are also being tested [ 105 ]. Among many new strategies, connexin peptide mimetics have demonstrated their usefulness, and biochemical modifications have greatly improved its isoform specificity, tissue specificity, cell membrane penetrance, and half-life [ 182 ]. After six decades of research on Cx43 and connexins, there is still a lot of Cx43 biology to explore.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Gap Junction-Dependent and -Independent Functions of Connexin43 in Biology

Zhu

2022

Biology

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For the first time in animal evolution, the emergence of gap junctions allowed direct exchanges of cellular substances for communication between two cells. Innexin proteins constituted primordial gap junctions until the connexin protein emerged in deuterostomes and took over the gap junction function. After hundreds of millions of years of gene duplication, the connexin gene family now comprises 21 members in the human genome. Notably, GJA1, which encodes the Connexin43 protein, is one of the most widely expressed and commonly studied connexin genes. The loss of Gja1 in mice leads to swelling and a blockage of the right ventricular outflow tract and death of the embryos at birth, suggesting a vital role of Connexin43 gap junction in heart development. Since then, the importance of Connexin43-mediated gap junction function has been constantly expanded to other types of cells. Other than forming gap junctions, Connexin43 can also form hemichannels to release or uptake small molecules from the environment or even mediate many physiological processes in a gap junction-independent manner on plasma membranes. Surprisingly, Connexin43 also localizes to mitochondria in the cell, playing important roles in mitochondrial potassium import and respiration. At the molecular level, Connexin43 mRNA and protein are processed with very distinct mechanisms to yield carboxyl-terminal fragments with different sizes, which have their unique subcellular localization and distinct biological activities. Due to many exciting advancements in Connexin43 research, this review aims to start with a brief introduction of Connexin43 and then focuses on updating our knowledge of its gap junction-independent functions.

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Mechanisms of Connexin Regulating Peptides

Cited by 18 publications

References 213 publications

Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers

Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers

The Role of Connexin Hemichannels in Inflammatory Diseases

Gap Junction-Dependent and -Independent Functions of Connexin43 in Biology

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