The role of gap junctions in inflammatory and neoplastic disorders (Review)

Wong, Pui; Laxton, Victoria; Srivastava, Saurabh; Chan, Yawen; Tse, Gary

doi:10.3892/ijmm.2017.2859

Cited by 38 publications

(31 citation statements)

References 148 publications

(146 reference statements)

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“…Damage to peripheral nerves or the spinal cord is often accompanied by neuropathic pain, which is a complex, chronic pain state (Jeon and Youn 2015). The ability of gap junction proteins to regulate immune responses, cell proliferation, migration, apoptosis, and carcinogenesis makes them attractive therapeutic targets for treating inflammatory and neoplastic disorders in different organ systems (Wong et al 2017). TRP channels can be modulated indirectly by inflammatory mediators such as PGE2, bradykinin, ATP, NGF, and proinflammatory cytokines that are generated during tissue injury (Vay et al 2012), and they play a role in neuropathic pain (Marwaha et al 2016).…”

Section: Discussionmentioning

confidence: 99%

In silico target network analysis of de novo-discovered, tick saliva-specific microRNAs reveals important combinatorial effects in their interference with vertebrate host physiology

Hackenberg

Langenberger

Schwarz

et al. 2017

RNA

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The hard tick is an important disease vector whose salivary secretions mediate blood-feeding success on vertebrate hosts, including humans. Here we describe the expression profiles and downstream analysis of de novo-discovered microRNAs (miRNAs) expressed in salivary glands and saliva. Eleven tick-derived libraries were sequenced to produce 67,375,557 Illumina reads. De novo prediction yielded 67 bona fide miRNAs out of which 35 are currently not present in miRBase. We report for the first time the presence of microRNAs in tick saliva, obtaining furthermore molecular indicators that those might be of exosomal origin. Ten out of these microRNAs are at least 100 times more represented in saliva. For the four most expressed microRNAs from this subset, we analyzed their combinatorial effects upon their host transcriptome using a novel in silico target network approach. We show that only the inclusion of combinatorial effects reveals the functions in important pathways related to inflammation and pain sensing. A control set of highly abundant microRNAs in both saliva and salivary glands indicates no significant pathways and a far lower number of shared target genes. Therefore, the analysis of miRNAs from pure tick saliva strongly supports the hypothesis that tick saliva miRNAs can modulate vertebrate host homeostasis and represents the first direct evidence of tick miRNA-mediated regulation of vertebrate host gene expression at the tick-host interface. As such, the herein described miRNAs may support future drug discovery and development projects that will also experimentally question their predicted molecular targets in the vertebrate host.

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Section: Discussionmentioning

confidence: 99%

In silico target network analysis of de novo-discovered, tick saliva-specific microRNAs reveals important combinatorial effects in their interference with vertebrate host physiology

Hackenberg

Langenberger

Schwarz

et al. 2017

RNA

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“…Gap junctions are a key determinant in facilitating this process by allowing a direct exchange of small metabolites, second messengers, and ions [1]. In non-excitable tissue, gap junctions are involved in many physiological events, including cell differentiation, synchronization, and immune response [1][2][3][4]. This specialized intercellular coupling can also be found in excitable tissue, such as cardiac myocytes, where processes including rapid synchronization and facilitation of action potential propagation occur [5].…”

Section: Introductionmentioning

confidence: 99%

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

Cocozzelli

White

2019

IJMS

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Gap junctional channels are specialized components of the cellular membrane that allow the intercellular passage of small metabolites, ions, and second messengers to maintain homeostasis. They are comprised of members of the connexin gene family that encode a wide array of proteins that are expressed in nearly every tissue type. Cx43 is perceived to be the most broadly expressed connexin in humans, with several genetic skin diseases being linked to Cx43 mutations specifically. These mutations, in large, produce a gain of functional hemichannels that contribute to the phenotypes of Erythrokeratoderma Variabilis et Progressiva (EKVP), Palmoplantar Keratodemra Congenital Alopecia-1 (PPKCA1), and others that produce large conductance and increased permselectivity in otherwise quiescent structures. Gaining functional hemichannels can have adverse effects in the skin, inducing apoptosis via Ca2+ overload or increased ATP permeability. Here, we review the link between Cx43 and skin disease. We aim to provide insight into the mechanisms regulating the normal and pathophysiological gating of these essential proteins, as well as address current therapeutic strategies. We also demonstrate that transient transfection of neuro-2a (N2a) cells with mutant Cx43 cDNA resulted in increased hemichannel activity compared to wild-type Cx43 and untransfected cells, which is consistent with other studies in the current literature.

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“…Numerous human disorders are characterized by the loss of gap junction channels, and they span tissues including the skin, heart, joints, teeth, and immune system, to name just a few (Jongsma and Wilders, 2000;van Steensel, 2004;Kleopa and Scherer, 2006;Laird, 2006Laird, , 2010Wong et al, 2017;Donahue et al, 2018). Indeed, the leading cause of deafness is due to the loss of Connexins expressed in the ear, which is currently, and extremely controversially, earmarked for a possible human CRISPR trial (Batissoco et al, 2018;Cyranoski, 2019).…”

Section: Discussionmentioning

confidence: 99%

Understanding the Molecular and Cell Biological Mechanisms of Electrical Synapse Formation

2020

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In this review article, we will describe the recent advances made towards understanding the molecular and cell biological mechanisms of electrical synapse formation. New evidence indicates that electrical synapses, which are gap junctions between neurons, can have complex molecular compositions including protein asymmetries across joined cells, diverse morphological arrangements, and overlooked similarities with other junctions, all of which indicate new potential roles in neurodevelopmental disease. Aquatic organisms, and in particular the vertebrate zebrafish, have proven to be excellent models for elucidating the molecular mechanisms of electrical synapse formation. Zebrafish will serve as our main exemplar throughout this review and will be compared with other model organisms. We highlight the known cell biological processes that build neuronal gap junctions and compare these with the assemblies of adherens junctions, tight junctions, non-neuronal gap junctions, and chemical synapses to explore the unknown frontiers remaining in our understanding of the critical and ubiquitous electrical synapse.

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The role of gap junctions in inflammatory and neoplastic disorders (Review)

Cited by 38 publications

References 148 publications

In silico target network analysis of de novo-discovered, tick saliva-specific microRNAs reveals important combinatorial effects in their interference with vertebrate host physiology

In silico target network analysis of de novo-discovered, tick saliva-specific microRNAs reveals important combinatorial effects in their interference with vertebrate host physiology

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

Understanding the Molecular and Cell Biological Mechanisms of Electrical Synapse Formation

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