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Chemical Regulation of Gap Junction Channels and Hemichannels 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 14456

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Special Issue Editor

Prof. Dr. Camillo Peracchia

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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

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our 2020 Special Issue “Chemical Regulation of Gap Junction Channels and Hemichannels”.

Neighboring cells directly exchange small cytosolic molecules via cell–cell channels clustered at gap junctions. Direct cell communication provides a fundamental mechanism for coordinating numerous cellular activities. Conversely, impaired communication causes many diseases. Each 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 and innexins). Gap junction channels are regulated by a gating mechanism sensitive to changes in cytosolic calcium (Ca ²⁺_i) and pH_i. Early studies reported that only [Ca²⁺]_i in the micromolar range affects gating. This would discard the role of Ca²⁺_i as fine modulator of cell coupling. More recently, however, the effectiveness of calmodulin-mediated nanomolar [Ca²⁺]_i in cell–cell channel and hemichannel gating has been widely reported, suggesting that the permeability of connexin and innexin channels and hemichannels is finely modulated. Indeed, in some cells, such as those expressing connexin45, some channels are closed even at resting [Ca²⁺]_i.

The relevance of the fine modulation of connexin and innexin channels and hemichannels to cell function in health and disease indicates that detailed knowledge of channel gating mechanisms is extremely important. Indeed, recent evidence for a dozen of human CaM missense mutations found in patients with severe cardiac arrhythmias should encourage careful studies on the role of these CaM mutants in altering cell communication via gap junction channels in diseases affecting the heart and other organs.

This is the primary goal of this Special Issue #2.

Prof. Dr. Camillo Peracchia
Guest Editor

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Keywords

gap junctions
connexins
channel gating
calcium
pH
calmodulin
cell communication
cell–cell coupling

Published Papers (6 papers)

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Research

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20 pages, 4762 KiB

Open AccessArticle

TNF-α Plus IL-1β Induces Opposite Regulation of Cx43 Hemichannels and Gap Junctions in Mesangial Cells through a RhoA/ROCK-Dependent Pathway

by Claudia M. Lucero, Lucas Marambio-Ruiz, Javiera Balmazabal, Juan Prieto-Villalobos, Marcelo León, Paola Fernández, Juan A. Orellana, Victoria Velarde, Juan C. Sáez and Gonzalo I. Gómez

Int. J. Mol. Sci. 2022, 23(17), 10097; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710097 - 03 Sep 2022

Cited by 4 | Viewed by 2315

Abstract

Connexin 43 (Cx43) is expressed in kidney tissue where it forms hemichannels and gap junction channels. However, the possible functional relationship between these membrane channels and their role in damaged renal cells remains unknown. Here, analysis of ethidium uptake and thiobarbituric acid reactive species revealed that treatment with TNF-α plus IL-1β increases Cx43 hemichannel activity and oxidative stress in MES-13 cells (a cell line derived from mesangial cells), and in primary mesangial cells. The latter was also accompanied by a reduction in gap junctional communication, whereas Western blotting assays showed a progressive increase in phosphorylated MYPT (a target of RhoA/ROCK) and Cx43 upon TNF-α/IL-1β treatment. Additionally, inhibition of RhoA/ROCK strongly antagonized the TNF-α/IL-1β-induced activation of Cx43 hemichannels and reduction in gap junctional coupling. We propose that activation of Cx43 hemichannels and inhibition of cell–cell coupling during pro-inflammatory conditions could contribute to oxidative stress and damage of mesangial cells via the RhoA/ROCK pathway. Full article

(This article belongs to the Special Issue Chemical Regulation of Gap Junction Channels and Hemichannels 2.0)

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12 pages, 4626 KiB

Open AccessArticle

GABA_BR Modulation of Electrical Synapses and Plasticity in the Thalamic Reticular Nucleus

by Huaixing Wang and Julie S. Haas

Int. J. Mol. Sci. 2021, 22(22), 12138; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212138 - 09 Nov 2021

Cited by 1 | Viewed by 1822

Abstract

Two distinct types of neuronal activity result in long-term depression (LTD) of electrical synapses, with overlapping biochemical intracellular signaling pathways that link activity to synaptic strength, in electrically coupled neurons of the thalamic reticular nucleus (TRN). Because components of both signaling pathways can also be modulated by GABA_B receptor activity, here we examined the impact of GABA_B receptor activation on the two established inductors of LTD in electrical synapses. Recording from patched pairs of coupled rat neurons in vitro, we show that GABA_B receptor inactivation itself induces a modest depression of electrical synapses and occludes LTD induction by either paired bursting or metabotropic glutamate receptor (mGluR) activation. GABA_B activation also occludes LTD from either paired bursting or mGluR activation. Together, these results indicate that afferent sources of GABA, such as those from the forebrain or substantia nigra to the reticular nucleus, gate the induction of LTD from either neuronal activity or afferent glutamatergic receptor activation. These results add to a growing body of evidence that the regulation of thalamocortical transmission and sensory attention by TRN is modulated and controlled by other brain regions. Significance: We show that electrical synapse plasticity is gated by GABA_B receptors in the thalamic reticular nucleus. This effect is a novel way for afferent GABAergic input from the basal ganglia to modulate thalamocortical relay and is a possible mediator of intra-TRN inhibitory effects. Full article

(This article belongs to the Special Issue Chemical Regulation of Gap Junction Channels and Hemichannels 2.0)

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17 pages, 3287 KiB

Open AccessArticle

Ouabain Enhances Gap Junctional Intercellular Communication by Inducing Paracrine Secretion of Prostaglandin E2

by Alejandro Ogazon del Toro, Lidia Jimenez, Mauricio Serrano Rubi, Marcelino Cereijido and Arturo Ponce

Int. J. Mol. Sci. 2021, 22(12), 6244; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126244 - 10 Jun 2021

Cited by 2 | Viewed by 2024

Abstract

Ouabain is a cardiac glycoside that has been described as a hormone, with interesting effects on epithelial physiology. We have shown previously that ouabain induces gap junctional intercellular communication (GJIC) in wild, sensitive cells (MDCK-S), but not in cells that have become insensitive (MDCK-I) by modifying their Na⁺-K⁺-ATPase. We have also demonstrated that prostaglandin E2 (PGE2) is able to induce increased GJIC by a mechanism other than ouabain, that does not depend on Na⁺-K⁺-ATPase. In this work we show, by dye transfer assays, that when MDCK-S and MDCK-I are randomly mixed, to form monolayers, the latter stablish GJIC, because of stimulation by a compound released to the extracellular media, by MDCK-S cells, after treatment with ouabain, as evidenced by the fact that monolayers of only MDCK-I cells, treated with a conditioned medium (CM) that is obtained after incubation of MDCK-S monolayers with ouabain, significantly increase their GJIC. The further finding that either (1) pre-treatment with COX-2 inhibitors or (2) addition to CM of antagonists of EP2 receptor abolish CM’s ability to induce GJIC in MDCK-I monolayers indicate that PGE2 is the GJIC-inducing compound. Therefore, these results indicate that, in addition to direct stimulation, mediated by Na⁺-K⁺-ATPase, ouabain enhances GJIC indirectly through the paracrine production of PGE2. Full article

(This article belongs to the Special Issue Chemical Regulation of Gap Junction Channels and Hemichannels 2.0)

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Review

Jump to: Research

24 pages, 4530 KiB

Open AccessReview

Direct Cell-Cell Communication via Membrane Pores, Gap Junction Channels, and Tunneling Nanotubes: Medical Relevance of Mitochondrial Exchange

by Eliseo Eugenin, Enrico Camporesi and Camillo Peracchia

Int. J. Mol. Sci. 2022, 23(11), 6133; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116133 - 30 May 2022

Cited by 8 | Viewed by 3049

Abstract

The history of direct cell-cell communication has evolved in several small steps. First discovered in the 1930s in invertebrate nervous systems, it was thought at first to be an exception to the “cell theory”, restricted to invertebrates. Surprisingly, however, in the 1950s, electrical cell-cell communication was also reported in vertebrates. Once more, it was thought to be an exception restricted to excitable cells. In contrast, in the mid-1960s, two startling publications proved that virtually all cells freely exchange small neutral and charged molecules. Soon after, cell-cell communication by gap junction channels was reported. While gap junctions are the major means of cell-cell communication, in the early 1980s, evidence surfaced that some cells might also communicate via membrane pores. Questions were raised about the possible artifactual nature of the pores. However, early in this century, we learned that communication via membrane pores exists and plays a major role in medicine, as the structures involved, “tunneling nanotubes”, can rescue diseased cells by directly transferring healthy mitochondria into compromised cells and tissues. On the other hand, pathogens/cancer could also use these communication systems to amplify pathogenesis. Here, we describe the evolution of the discovery of these new communication systems and the potential therapeutic impact on several uncurable diseases. Full article

(This article belongs to the Special Issue Chemical Regulation of Gap Junction Channels and Hemichannels 2.0)

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17 pages, 2429 KiB

Open AccessReview

Gap Junction Channelopathies and Calmodulinopathies. Do Disease-Causing Calmodulin Mutants Affect Direct Cell–Cell Communication?

by Camillo Peracchia

Int. J. Mol. Sci. 2021, 22(17), 9169; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179169 - 25 Aug 2021

Cited by 3 | Viewed by 2040

Abstract

The cloning of connexins cDNA opened the way to the field of gap junction channelopathies. Thus far, at least 35 genetic diseases, resulting from mutations of 11 different connexin 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 been paid to the potential diseases of cell–cell communication caused by mutations of Cx-associated molecules. An important Cx accessory protein is calmodulin (CaM), which is the major regulator of gap junction channel gating and a molecule relevant to gap junction formation. 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. The major goal of this review is to raise awareness on the likely role of CaM mutations in defects of gap junction mediated cell communication. Our studies have demonstrated that certain CaM mutants affect gap junction channel gating or expression, so it would not be surprising to learn that CaM mutations known to cause diseases also affect cell communication mediated by gap junction channels. Full article

(This article belongs to the Special Issue Chemical Regulation of Gap Junction Channels and Hemichannels 2.0)

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14 pages, 2403 KiB

Open AccessReview

The Roles of Calmodulin and CaMKII in Cx36 Plasticity

by Georg R. Zoidl and David C. Spray

Int. J. Mol. Sci. 2021, 22(9), 4473; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094473 - 25 Apr 2021

Cited by 7 | Viewed by 2451

Abstract

Anatomical and electrophysiological evidence that gap junctions and electrical coupling occur between neurons was initially confined to invertebrates and nonmammals and was thought to be a primitive form of synaptic transmission. More recent studies revealed that electrical communication is common in the mammalian central nervous system (CNS), often coexisting with chemical synaptic transmission. The subsequent progress indicated that electrical synapses formed by the gap junction protein connexin-36 (Cx36) and its paralogs in nonmammals constitute vital elements in mammalian and fish synaptic circuitry. They govern the collective activity of ensembles of coupled neurons, and Cx36 gap junctions endow them with enormous adaptive plasticity, like that seen at chemical synapses. Moreover, they orchestrate the synchronized neuronal network activity and rhythmic oscillations that underlie the fundamental integrative processes, such as memory and learning. Here, we review the available mechanistic evidence and models that argue for the essential roles of calcium, calmodulin, and the Ca²⁺/calmodulin-dependent protein kinase II in integrating calcium signals to modulate the strength of electrical synapses through interactions with the gap junction protein Cx36. Full article

(This article belongs to the Special Issue Chemical Regulation of Gap Junction Channels and Hemichannels 2.0)

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