scholarly journals Cardiac Connexin-43 Hemichannels and Pannexin1 Channels: Provocative Antiarrhythmic Targets

2020 ◽  
Vol 22 (1) ◽  
pp. 260
Author(s):  
Katarina Andelova ◽  
Tamara Egan Benova ◽  
Barbara Szeiffova Bacova ◽  
Matus Sykora ◽  
Natalia Jorgelina Prado ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Purinergic Signaling ◽  
Redox Status ◽  
Myocardial Contraction ◽  
Current Evidence ◽  
Cardiac Arrhythmogenesis ◽  
Channel Opening ◽  
Inhibitory Agents ◽  
Molecular Signals ◽  
Extracellular Environment

Cardiac connexin-43 (Cx43) creates gap junction channels (GJCs) at intercellular contacts and hemi-channels (HCs) at the peri-junctional plasma membrane and sarcolemmal caveolae/rafts compartments. GJCs are fundamental for the direct cardiac cell-to-cell transmission of electrical and molecular signals which ensures synchronous myocardial contraction. The HCs and structurally similar pannexin1 (Panx1) channels are active in stressful conditions. These channels are essential for paracrine and autocrine communication through the release of ions and signaling molecules to the extracellular environment, or for uptake from it. The HCs and Panx1 channel-opening profoundly affects intracellular ionic homeostasis and redox status and facilitates via purinergic signaling pro-inflammatory and pro-fibrotic processes. These conditions promote cardiac arrhythmogenesis due to the impairment of the GJCs and selective ion channel function. Crosstalk between GJCs and HCs/Panx1 channels could be crucial in the development of arrhythmogenic substrates, including fibrosis. Despite the knowledge gap in the regulation of these channels, current evidence indicates that HCs and Panx1 channel activation can enhance the risk of cardiac arrhythmias. It is extremely challenging to target HCs and Panx1 channels by inhibitory agents to hamper development of cardiac rhythm disorders. Progress in this field may contribute to novel therapeutic approaches for patients prone to develop atrial or ventricular fibrillation.

scholarly journals HIV gp120 Protein Increases the Function of Connexin 43 Hemichannels and Pannexin-1 Channels in Astrocytes: Repercussions on Astroglial Function

2020 ◽  
Vol 21 (7) ◽  
pp. 2503 ◽  
Author(s):  
Rosario Gajardo-Gómez ◽  
Cristian A. Santibañez ◽  
Valeria C. Labra ◽  
Gonzalo I. Gómez ◽  
Eliseo A. Eugenin ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Purinergic Signaling ◽  
Atp Release ◽  
P38 Map Kinase ◽  
Motor Deficits ◽  
Pannexin 1 ◽  
Channel Opening ◽  
Wide Range

At least half of human immunodeficiency virus (HIV)-infected individuals suffer from a wide range of cognitive, behavioral and motor deficits, collectively known as HIV-associated neurocognitive disorders (HAND). The molecular mechanisms that amplify damage within the brain of HIV-infected individuals are unknown. Recently, we described that HIV augments the opening of connexin-43 (Cx43) hemichannels in cultured human astrocytes, which result in the collapse of neuronal processes. Whether HIV soluble viral proteins such as gp120, can regulate hemichannel opening in astrocytes is still ignored. These channels communicate the cytosol with the extracellular space during pathological conditions. We found that gp120 enhances the function of both Cx43 hemichannels and pannexin-1 channels in mouse cortical astrocytes. These effects depended on the activation of IL-1β/TNF-α, p38 MAP kinase, iNOS, cytoplasmic Ca2+ and purinergic signaling. The gp120-induced channel opening resulted in alterations in Ca2+ dynamics, nitric oxide production and ATP release. Although the channel opening evoked by gp120 in astrocytes was reproduced in ex vivo brain preparations, these responses were heterogeneous depending on the CA1 region analyzed. We speculate that soluble gp120-induced activation of astroglial Cx43 hemichannels and pannexin-1 channels could be crucial for the pathogenesis of HAND.

scholarly journals GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans

2019 ◽  
Vol 180 (2) ◽  
pp. R59-R71 ◽  
Author(s):  
Aimilia Eirini Papathanasiou ◽  
Eric Nolen-Doerr ◽  
Olivia M Farr ◽  
Christos S Mantzoros
Keyword(s):  
Energy Homeostasis ◽  
Endocrine System ◽  
Current Evidence ◽  
Energy Reserves ◽  
Neuroendocrine Function ◽  
Available Energy ◽  
Neuroendocrine Response ◽  
Leptin Deficiency ◽  
Molecular Signals ◽  
The Brain

The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.

NLRP3 inflammasome in ischemic stroke: As possible therapeutic target

2019 ◽  
Vol 14 (6) ◽  
pp. 574-591 ◽  
Author(s):  
Masoumeh Alishahi ◽  
Maryam Farzaneh ◽  
Farhoodeh Ghaedrahmati ◽  
Armin Nejabatdoust ◽  
Alireza Sarkaki ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Current Evidence ◽  
Related Factor ◽  
Type I ◽  
Micro Rnas ◽  
Extracellular Environment ◽  
Inflammasome Inhibitors

Inflammation is a devastating pathophysiological process during stroke, a devastating disease that is the second most common cause of death worldwide. Activation of the NOD-like receptor protein (NLRP3)-infammasome has been proposed to mediate inflammatory responses during ischemic stroke. Briefly, NLRP3 inflammasome activates caspase-1, which cleaves both pro-IL-1 and pro-IL-18 into their active pro-inflammatory cytokines that are released into the extracellular environment. Several NLRP3 inflammasome inhibitors have been promoted, including small molecules, type I interferon, micro RNAs, nitric oxide, and nuclear factor erythroid-2 related factor 2 (Nrf2), some of which are potentially efficacious clinically. This review will describe the structure and cellular signaling pathways of the NLRP3 inflammasome during ischemic stroke, and current evidence for NLRP3 inflammasome inhibitors.

scholarly journals Connexins and the kidney

2010 ◽  
Vol 298 (5) ◽  
pp. R1143-R1155 ◽  
Author(s):  
Fiona Hanner ◽  
Charlotte Mehlin Sorensen ◽  
Niels-Henrik Holstein-Rathlou ◽  
János Peti-Peterdi
Keyword(s):  
Gap Junctions ◽  
Purinergic Signaling ◽  
Renin Angiotensin System ◽  
Juxtaglomerular Apparatus ◽  
Tubuloglomerular Feedback ◽  
Current Evidence ◽  
Morphological Evidence ◽  
Renal Vasculature ◽  
Angiotensin System ◽  
Major Function

Connexins (Cxs) are widely-expressed proteins that form gap junctions in most organs, including the kidney. In the renal vasculature, Cx37, Cx40, Cx43, and Cx45 are expressed, with predominant expression of Cx40 in the endothelial cells and Cx45 in the vascular smooth muscle cells. In the tubules, there is morphological evidence for the presence of gap junction plaques only in the proximal tubules. In the distal nephron, Cx30, Cx30.3, and Cx37 are expressed, but it is not known whether they form gap junctions connecting neighboring cells or whether they primarily act as hemichannels. As in other systems, the major function of Cxs in the kidney appears to be intercellular communication, although they may also form hemichannels that allow cellular secretion of large signaling molecules. Renal Cxs facilitate vascular conduction, juxtaglomerular apparatus calcium signaling, and tubular purinergic signaling. Accordingly, current evidence points to roles for these Cxs in several important regulatory mechanisms in the kidney, including the renin angiotensin system, tubuloglomerular feedback, and salt and water reabsorption. At the systemic level, renal Cxs may help regulate blood pressure and may be involved in hypertension and diabetes.

scholarly journals Mechanisms of ATP release in pain: role of pannexin and connexin channels

2021 ◽  
Author(s):  
Manuel F. Muñoz ◽  
Theanne N. Griffith ◽  
Jorge E. Contreras
Keyword(s):  
Purinergic Receptors ◽  
Pain Treatment ◽  
Purinergic Signaling ◽  
Atp Release ◽  
Current Evidence ◽  
Pain Processing ◽  
Potential Threat ◽  
Acute Response ◽  
Outstanding Question

AbstractPain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.

scholarly journals The Multifaceted Role of Connexins in Tumor Microenvironment Initiation and Maintaining

2021 ◽  
Author(s):  
Olga Kutova ◽  
Anton Pospelov ◽  
Irina Balalaeva
Keyword(s):  
Tumor Microenvironment ◽  
Purinergic Signaling ◽  
Large Body ◽  
Molecular Transport ◽  
Tumor Tissues ◽  
Cancer Initiation ◽  
Different Types ◽  
Channel Assembly ◽  
Extracellular Environment

The modern paradigm of studying the processes of carcinogenesis and vital activity of tumor tissues implies increased attention to constituents of tumor microenvironment (TME) and their interactions. These interactions between the cells in TME can be mediated via protein junctions of different types. Connexins (Cnxs) are one of the major contributors to intercellular communication. They form gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc. between neighboring tumor cells as well as between tumor and stromal cells. Cnx hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, Cnxs were reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. Pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization and functionality as well as channel assembly and non-channel functions. In this review we have summarized the data on the Cnxs contribution in TME and to the cancer initiation and progression.

A dual voltage clamp technique to study gap junction hemichannels in astrocytes cultured from neonatal rodent spinal cords

2021 ◽  
Author(s):  
Juan Mauricio Garre ◽  
Feliksas F Bukauskas ◽  
Michael V Bennett
Keyword(s):  
Voltage Clamp ◽  
Connexin 43 ◽  
Single Channel ◽  
Purinergic Signaling ◽  
Atp Release ◽  
Single Channels ◽  
P2x7 Receptors ◽  
Voltage Clamp Technique ◽  
Pannexin 1 ◽  
Clamp Technique

Astrocytes express surface channels involved in purinergic signaling, and among these channels, pannexin-1 (Px1) and connexin-43 (Cx43) hemichannels (HCs) mediate ATP release that acts directly, or through its derivatives, on neurons and glia via purinergic receptors. Although HCs are functional, i.e., open and close, under physiological and pathological conditions, single channel conductance of Px1 HCs is not well defined. Here, we developed a dual voltage clamp technique in HeLa cells overexpressing human Px1-YFP, and then applied this system to rodent spinal astrocytes. Single channels were recorded in cell attached patches and evoked with ramp cycles of 2 s duration and -/+ 80-100 mV amplitude or rectangular pulses through another pipette in whole cell clamp. Conductance of Px1 HC openings recorded during ramp stimuli ranged 25-110 pS. Based on their single channel conductances, Px1 HCs could be distinguished from Cx43 HCs and P2X7 receptors (P2X7Rs) in spinal astrocytes during dual voltage clamp experiments. Furthermore, we found that single channel activity of Cx43 HCs and P2X7Rs was increased, and that of Px1 HCs was decreased, in spinal astrocytes treated for 7h with FGF-1, a growth factor implicated in neurodevelopment, repair and inflammation.

scholarly journals Real-Time In Vivo Imaging of Mouse Left Ventricle Reveals Fluctuating Movements of the Intercalated Discs

Nanomaterials ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 532
Author(s):  
Fuyu Kobirumaki-Shimozawa ◽  
Tomohiro Nakanishi ◽  
Togo Shimozawa ◽  
Takako Terui ◽  
Kotaro Oyama ◽  
...  
Keyword(s):  
Real Time ◽  
Connexin 43 ◽  
Myocardial Contraction ◽  
Confocal Imaging ◽  
Electronic Conduction ◽  
Mouse Heart ◽  
Living Mouse ◽  
Small Change ◽  
Cardiac Sodium Channels

Myocardial contraction is initiated by action potential propagation through the conduction system of the heart. It has been thought that connexin 43 in the gap junctions (GJ) within the intercalated disc (ID) provides direct electric connectivity between cardiomyocytes (electronic conduction). However, recent studies challenge this view by providing evidence that the mechanosensitive cardiac sodium channels Nav1.5 localized in perinexii at the GJ edge play an important role in spreading action potentials between neighboring cells (ephaptic conduction). In the present study, we performed real-time confocal imaging of the CellMask-stained ID in the living mouse heart in vivo. We found that the ID structure was not rigid. Instead, we observed marked flexing of the ID during propagation of contraction from cell to cell. The variation in ID length was between ~30 and ~42 μm (i.e., magnitude of change, ~30%). In contrast, tracking of α-actinin-AcGFP revealed a comparatively small change in the lateral dimension of the transitional junction near the ID (i.e., magnitude of change, ~20%). The present findings suggest that, when the heart is at work, mechanostress across the perinexii may activate Nav1.5 by promoting ephaptic conduction in coordination with electronic conduction, and, thereby, efficiently transmitting excitation-contraction coupling between cardiomyocytes.

Gap junctions–guards of excitability

2015 ◽  
Vol 43 (3) ◽  
pp. 508-512 ◽  
Author(s):  
Line Waring Stroemlund ◽  
Christa Funch Jensen ◽  
Klaus Qvortrup ◽  
Mario Delmar ◽  
Morten Schak Nielsen
Keyword(s):  
Sodium Channel ◽  
Crucial Role ◽  
Connexin 43 ◽  
Current Evidence ◽  
Intercalated Disc ◽  
Intercalated Discs ◽  
Cardiac Sodium Channel ◽  
Junctional Protein ◽  
Gap Junctional

Cardiomyocytes are connected by mechanical and electrical junctions located at the intercalated discs (IDs). Although these structures have long been known, it is becoming increasingly clear that their components interact. This review describes the involvement of the ID in electrical disturbances of the heart and focuses on the role of the gap junctional protein connexin 43 (Cx43). Current evidence shows that Cx43 plays a crucial role in organizing microtubules at the intercalated disc and thereby regulating the trafficking of the cardiac sodium channel NaV1.5 to the membrane.

scholarly journals Negative News: Cl− and HCO3− in the Vascular Wall

Physiology ◽  
2016 ◽  
Vol 31 (5) ◽  
pp. 370-383 ◽  
Author(s):  
Ebbe Boedtkjer ◽  
Vladimir V. Matchkov ◽  
Donna M. B. Boedtkjer ◽  
Christian Aalkjaer
Keyword(s):  
Protein Trafficking ◽  
Cardiovascular Health ◽  
Anion Channel ◽  
Vascular Wall ◽  
Current Evidence ◽  
Metabolic Disturbances ◽  
Vasomotor Function ◽  
Channel Opening ◽  
Health And Disease ◽  
Activity Of Enzymes

Cl− and HCO3− are the most prevalent membrane-permeable anions in the intra- and extracellular spaces of the vascular wall. Outwardly directed electrochemical gradients for Cl− and HCO3− permit anion channel opening to depolarize vascular smooth muscle and endothelial cells. Transporters and channels for Cl− and HCO3− also modify vascular contractility and structure independently of membrane potential. Transport of HCO3− regulates intracellular pH and thereby modifies the activity of enzymes, ion channels, and receptors. There is also evidence that Cl− and HCO3− transport proteins affect gene expression and protein trafficking. Considering the extensive implications of Cl− and HCO3− in the vascular wall, it is critical to understand how these ions are transported under physiological conditions and how disturbances in their transport can contribute to disease development. Recently, sensing mechanisms for Cl− and HCO3− have been identified in the vascular wall where they modify ion transport and vasomotor function, for instance, during metabolic disturbances. This review discusses current evidence that transport (e.g., via NKCC1, NBCn1, Ca2+-activated Cl− channels, volume-regulated anion channels, and CFTR) and sensing (e.g., via WNK and RPTPγ) of Cl− and HCO3− influence cardiovascular health and disease.

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