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Gap Junction Channels and Hemichannels in Health and Disease: 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 8458

Special Issue Editors

Prof. Dr. Camillo Peracchia

E-Mail Website
Guest Editor
School of Medicine and Dentistry 601 Elmwood Ave, University of Rochester Medical Center, Rochester, NY 14642, USA
Interests: Gap junctions; connexins; cell communication; calmodulin; calcium; channel gating
Special Issues, Collections and Topics in MDPI journals
Dr. Mario Bortolozzi

E-Mail Website
Guest Editor
1. Department of Physics and Astronomy "G. Galilei", University of Padua, 35131 Padova, Italy
2. Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy
Interests: biophysics; neuropathies; Charcot-Marie-Tooth; connexin 32; brain organoids; electrophysiology; live imaging; systems biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neighboring cells directly exchange small cytosolic molecules via cell–cell channels clustered at gap junctions. Gap junction-mediated cell communication is a very important mechanism that allows cells to coordinate numerous functions. Conversely, impaired cell–cell communication is known to cause many diseases.

Each gap junction channel is formed by the interaction of two hemichannels that create a hydrophilic pathway spanning the two plasma membranes and a narrow extracellular space (gap). In turn, each hemichannel is an oligomer of six proteins (connexins/innexins). Gap junction channels are regulated by a gating mechanism sensitive to changes in cytosolic calcium (Ca2+i) and pHi.

In the mid-1980s, the cloning of connexin/innexin cDNAs opened the way to the field of gap junction channelopathies. Thus far, at least thirty-five genetic diseases caused by mutations of eleven different connexins genes are known to cause numerous structural and functional defects in the central and peripheral nervous system as well as in the heart, skin, eyes, teeth, ears, bone, hair, nails, and lymphatic system.

While all of these diseases are due to connexin mutations, minimal attention has thus far been addressed to potential diseases caused by mutations of connexin-associated molecules. An important accessory of gap junctions is the protein calmodulin (CaM), which plays a role in channel gating and is relevant to gap junction formation as well. Recently, diseases caused by CaM mutations (calmodulinopathies) have been identified, but thus far, calmodulinopathy studies have not considered the potential effect of CaM mutations on gap junction function. Therefore, it is important to also raise awareness on the likely role of CaM mutations in defects of gap-junction-mediated cell communication.

Prof. Dr. Camillo Peracchia
Dr. Mario Bortolozzi
Guest Editors

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Keywords

  • gap junction channel
  • hemichannel
  • CaM
  • calmodulin

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Published Papers (6 papers)

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Research

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14 pages, 3504 KiB  
Communication
Connexin 43 Modulation in Human Chondrocytes, Osteoblasts and Cartilage Explants: Implications for Inflammatory Joint Disorders
by Elena Della Morte, Chiara Giannasi, Alice Valenza, Francesca Cadelano, Alessandro Aldegheri, Luigi Zagra, Stefania Niada and Anna Teresa Brini
Int. J. Mol. Sci. 2024, 25(15), 8547; https://doi.org/10.3390/ijms25158547 - 5 Aug 2024
Viewed by 2629
Abstract
Connexin 43 (Cx43) is crucial for the development and homeostasis of the musculoskeletal system, where it plays multifaceted roles, including intercellular communication, transcriptional regulation and influencing osteogenesis and chondrogenesis. Here, we investigated Cx43 modulation mediated by inflammatory stimuli involved in osteoarthritis, i.e., 10 [...] Read more.
Connexin 43 (Cx43) is crucial for the development and homeostasis of the musculoskeletal system, where it plays multifaceted roles, including intercellular communication, transcriptional regulation and influencing osteogenesis and chondrogenesis. Here, we investigated Cx43 modulation mediated by inflammatory stimuli involved in osteoarthritis, i.e., 10 ng/mL Tumor Necrosis Factor alpha (TNFα) and/or 1 ng/mL Interleukin-1 beta (IL-1β), in primary chondrocytes (CH) and osteoblasts (OB). Additionally, we explored the impact of synovial fluids from osteoarthritis patients in CH and cartilage explants, providing a more physio-pathological context. The effect of TNFα on Cx43 expression in cartilage explants was also assessed. TNFα downregulated Cx43 levels both in CH and OB (−73% and −32%, respectively), while IL-1β showed inconclusive effects. The reduction in Cx43 levels was associated with a significant downregulation of the coding gene GJA1 expression in OB only (−65%). The engagement of proteasome in TNFα-induced effects, already known in CH, was also observed in OB. TNFα treatment significantly decreased Cx43 expression also in cartilage explants. Of note, Cx43 expression was halved by synovial fluid in both CH and cartilage explants. This study unveils the regulation of Cx43 in diverse musculoskeletal cell types under various stimuli and in different contexts, providing insights into its modulation in inflammatory joint disorders. Full article
(This article belongs to the Special Issue Gap Junction Channels and Hemichannels in Health and Disease: 2nd Edition)
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Review

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20 pages, 6095 KiB  
Review
Calcium Role in Gap Junction Channel Gating: Direct Electrostatic or Calmodulin-Mediated?
by Camillo Peracchia
Int. J. Mol. Sci. 2024, 25(18), 9789; https://doi.org/10.3390/ijms25189789 - 10 Sep 2024
Viewed by 585
Abstract
The chemical gating of gap junction channels is mediated by cytosolic calcium (Ca2+i) at concentrations ([Ca2+]i) ranging from high nanomolar (nM) to low micromolar (µM) range. Since the proteins of gap junctions, connexins/innexins, lack high-affinity Ca [...] Read more.
The chemical gating of gap junction channels is mediated by cytosolic calcium (Ca2+i) at concentrations ([Ca2+]i) ranging from high nanomolar (nM) to low micromolar (µM) range. Since the proteins of gap junctions, connexins/innexins, lack high-affinity Ca2+-binding sites, most likely gating is mediated by a Ca2+-binding protein, calmodulin (CaM) being the best candidate. Indeed, the role of Ca2+-CaM in gating is well supported by studies that have tested CaM blockers, CaM expression inhibition, testing of CaM mutants, co-localization of CaM and connexins, existence of CaM-binding sites in connexins/innexins, and expression of connexins (Cx) mutants, among others. Based on these data, since 2000, we have published a Ca2+-CaM-cork gating model. Despite convincing evidence for the Ca2+-CaM role in gating, a recent study has proposed an alternative gating model that would involve a direct electrostatic Ca2+-connexin interaction. However, this study, which tested the effect of unphysiologically high [Ca2+]i on the structure of isolated junctions, reported that neither changes in the channel’s pore diameter nor connexin conformational changes are present, in spite of exposure of isolated gap junctions to [Ca2+]i as high at the 20 mM. In conclusion, data generated in the past four decades by multiple experimental approaches have clearly demonstrated the direct role of Ca2+-CaM in gap junction channel gating. Full article
(This article belongs to the Special Issue Gap Junction Channels and Hemichannels in Health and Disease: 2nd Edition)
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18 pages, 1095 KiB  
Review
Calcium Regulation of Connexin Hemichannels
by Erva Bayraktar, Diego Lopez-Pigozzi and Mario Bortolozzi
Int. J. Mol. Sci. 2024, 25(12), 6594; https://doi.org/10.3390/ijms25126594 - 15 Jun 2024
Cited by 2 | Viewed by 946
Abstract
Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions, HCs can form gap junction (GJ) channels, providing a direct diffusive path between neighbouring cells. In addition, unpaired HCs provide conduits for [...] Read more.
Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions, HCs can form gap junction (GJ) channels, providing a direct diffusive path between neighbouring cells. In addition, unpaired HCs provide conduits for the exchange of solutes between the cytoplasm and the extracellular milieu, including messenger molecules involved in paracrine signalling. The synergistic action of membrane potential and Ca2+ ions controls the gating of the large and relatively unselective pore of connexin HCs. The four orders of magnitude difference in gating sensitivity to the extracellular ([Ca2+]e) and the cytosolic ([Ca2+]c) Ca2+ concentrations suggests that at least two different Ca2+ sensors may exist. While [Ca2+]e acts as a spatial modulator of the HC opening, which is most likely dependent on the cell layer, compartment, and organ, [Ca2+]c triggers HC opening and the release of extracellular bursts of messenger molecules. Such molecules include ATP, cAMP, glutamate, NAD+, glutathione, D-serine, and prostaglandins. Lost or abnormal HC regulation by Ca2+ has been associated with several diseases, including deafness, keratitis ichthyosis, palmoplantar keratoderma, Charcot–Marie–Tooth neuropathy, oculodentodigital dysplasia, and congenital cataracts. The fact that both an increased and a decreased Ca2+ sensitivity has been linked to pathological conditions suggests that Ca2+ in healthy cells finely tunes the normal HC function. Overall, further investigation is needed to clarify the structural and chemical modifications of connexin HCs during [Ca2+]e and [Ca2+]c variations. A molecular model that accounts for changes in both Ca2+ and the transmembrane voltage will undoubtedly enhance our interpretation of the experimental results and pave the way for developing therapeutic compounds targeting specific HC dysfunctions. Full article
(This article belongs to the Special Issue Gap Junction Channels and Hemichannels in Health and Disease: 2nd Edition)
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15 pages, 938 KiB  
Review
Perspective and Therapeutic Potential of the Noncoding RNA–Connexin Axis
by Xinmu Li, Zhenzhen Wang and Naihong Chen
Int. J. Mol. Sci. 2024, 25(11), 6146; https://doi.org/10.3390/ijms25116146 - 2 Jun 2024
Viewed by 1038
Abstract
Noncoding RNAs (ncRNAs) are a class of nucleotide sequences that cannot be translated into peptides. ncRNAs can function post-transcriptionally by splicing complementary sequences of mRNAs or other ncRNAs or by directly engaging in protein interactions. Over the past few decades, the pervasiveness of [...] Read more.
Noncoding RNAs (ncRNAs) are a class of nucleotide sequences that cannot be translated into peptides. ncRNAs can function post-transcriptionally by splicing complementary sequences of mRNAs or other ncRNAs or by directly engaging in protein interactions. Over the past few decades, the pervasiveness of ncRNAs in cell physiology and their pivotal roles in various diseases have been identified. One target regulated by ncRNAs is connexin (Cx), a protein that forms gap junctions and hemichannels and facilitates intercellular molecule exchange. The aberrant expression and misdistribution of connexins have been implicated in central nervous system diseases, cardiovascular diseases, bone diseases, and cancer. Current databases and technologies have enabled researchers to identify the direct or indirect relationships between ncRNAs and connexins, thereby elucidating their correlation with diseases. In this review, we selected the literature published in the past five years concerning disorders regulated by ncRNAs via corresponding connexins. Among it, microRNAs that regulate the expression of Cx43 play a crucial role in disease development and are predominantly reviewed. The distinctive perspective of the ncRNA–Cx axis interprets pathology in an epigenetic manner and is expected to motivate research for the development of biomarkers and therapeutics. Full article
(This article belongs to the Special Issue Gap Junction Channels and Hemichannels in Health and Disease: 2nd Edition)
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28 pages, 7108 KiB  
Review
Gap Junction Channel Regulation: A Tale of Two Gates—Voltage Sensitivity of the Chemical Gate and Chemical Sensitivity of the Fast Voltage Gate
by Camillo Peracchia
Int. J. Mol. Sci. 2024, 25(2), 982; https://doi.org/10.3390/ijms25020982 - 12 Jan 2024
Cited by 3 | Viewed by 1043
Abstract
Gap junction channels are regulated by gates sensitive to cytosolic acidification and trans-junctional voltage (Vj). We propose that the chemical gate is a calmodulin (CaM) lobe. The fast-Vj gate is made primarily by the connexin’s NH2-terminus domain (NT). The chemical gate [...] Read more.
Gap junction channels are regulated by gates sensitive to cytosolic acidification and trans-junctional voltage (Vj). We propose that the chemical gate is a calmodulin (CaM) lobe. The fast-Vj gate is made primarily by the connexin’s NH2-terminus domain (NT). The chemical gate closes the channel slowly and completely, while the fast-Vj gate closes the channel rapidly but incompletely. The chemical gate closes with increased cytosolic calcium concentration [Ca2+]i and with Vj gradients at Vj’s negative side. In contrast, the fast-Vj gate closes at the positive or negative side of Vj depending on the connexin (Cx) type. Cxs with positively charged NT close at Vj’s negative side, while those with negatively charged NT close at Vj’s positive side. Cytosolic acidification alters in opposite ways the sensitivity of the fast-Vj gate: it increases the Vj sensitivity of negative gaters and decreases that of positive gaters. While the fast-Vj gate closes and opens instantaneously, the chemical gate often shows fluctuations, likely to reflect the shifting of the gate (CaM’s N-lobe) in and out of the channel’s pore. Full article
(This article belongs to the Special Issue Gap Junction Channels and Hemichannels in Health and Disease: 2nd Edition)
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18 pages, 1203 KiB  
Review
Connexins Control Glial Inflammation in Various Neurological Diseases
by Ryo Yamasaki
Int. J. Mol. Sci. 2023, 24(23), 16879; https://doi.org/10.3390/ijms242316879 - 28 Nov 2023
Cited by 1 | Viewed by 1501
Abstract
Connexins (Cxs) form gap junctions through homotypic/heterotypic oligomerization. Cxs are initially synthesized in the endoplasmic reticulum, then assembled as hexamers in the Golgi apparatus before being integrated into the cell membrane as hemichannels. These hemichannels remain closed until they combine to create gap [...] Read more.
Connexins (Cxs) form gap junctions through homotypic/heterotypic oligomerization. Cxs are initially synthesized in the endoplasmic reticulum, then assembled as hexamers in the Golgi apparatus before being integrated into the cell membrane as hemichannels. These hemichannels remain closed until they combine to create gap junctions, directly connecting neighboring cells. Changes in the intracellular or extracellular environment are believed to trigger the opening of hemichannels, creating a passage between the inside and outside of the cell. The size of the channel pore depends on the Cx isoform and cellular context-specific effects such as posttranslational modifications. Hemichannels allow various bioactive molecules, under ~1 kDa, to move in and out of the host cell in the direction of the electrochemical gradient. In this review, we explore the fundamental roles of Cxs and their clinical implications in various neurological dysfunctions, including hereditary diseases, ischemic brain disorders, degenerative conditions, demyelinating disorders, and psychiatric illnesses. The influence of Cxs on the pathomechanisms of different neurological disorders varies depending on the circumstances. Hemichannels are hypothesized to contribute to proinflammatory effects by releasing ATP, adenosine, glutamate, and other bioactive molecules, leading to neuroglial inflammation. Modulating Cxs’ hemichannels has emerged as a promising therapeutic approach. Full article
(This article belongs to the Special Issue Gap Junction Channels and Hemichannels in Health and Disease: 2nd Edition)
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