Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications

Totland, Max Z.; Rasmussen, Nikoline Lander; Knudsen, Lars Mørland; Leithe, Edward

doi:10.1007/s00018-019-03285-0

Cited by 102 publications

(77 citation statements)

References 164 publications

(217 reference statements)

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“…Therefore, it is conceivable that variations in the levels of interaction with LC3 among the different connexins tested reflect differences in the amino acids surrounding the LIR motif on each connexin. Importantly, we also show that all of these connexins are modified with ubiquitin, which, to our knowledge, has never been reported for Cx37, Cx46 and Cx50 [4,19]. Having established that connexin binds to LC3B, we then investigated whether the putative LIR motif found in the amino terminal of these proteins was important to mediate this interaction.…”

Section: The Connexin Protein Family Contains a Conserved Lir Motif Imentioning

confidence: 52%

A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins

Catarino

Ribeiro-Rodrigues

Ferreira

et al. 2020

Cells

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Gap junctions (GJ) are specialized cell-cell contacts formed by connexins (Cxs), which provide direct communication between adjacent cells. Cx43 ubiquitination has been suggested to induce the internalization of GJs, as well as the recruitment of the autophagy receptor p62 to mediate binding to LC3B and degradation by macroautophagy. In this report, we describe a functional LC3 interacting region (LIR), present in the amino terminal of most Cx protein family members, which can mediate the autophagy degradation of Cx43 without the need of ubiquitin. Mutation of the LIR motif on Cx37, Cx43, Cx46 and Cx50 impairs interaction with LC3B and GABARAP without compromising protein ubiquitination. Through in vitro protein-protein interaction assays, we demonstrate that this LIR motif is required for the binding of Cx43 to LC3B and GABARAP. Overall, our findings describe an alternative mechanism whereby Cxs interact with LC3/GABARAP proteins, envisioning a new model for the autophagy degradation of connexins.

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Section: The Connexin Protein Family Contains a Conserved Lir Motif Imentioning

confidence: 52%

A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins

Catarino

Ribeiro-Rodrigues

Ferreira

et al. 2020

Cells

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“…Indeed, our previous study found that mechanical unloading changed the concentration of extracellular Sost but not the intracellular Sost in the femur in vivo using a transmission electron microscopy ( Osumi et al, 2020 ). On the other hand, the discrepancy between the mRNA and protein expression of Cx43 may be due to the post-translational modifications, since the mechanical stimulation changed the phosphorylation status of Cx43 ( Genetos et al, 2007 ; Qin et al, 2020 ) and Cx43 degradation is controlled by complex crosstalk between connexin phosphorylation and ubiquitination ( Totland et al, 2020 ). Ser368 of Cx43 is phosphorylated by protein kinase C (PKC), which decreases cell-to-cell communication ( Lampe et al, 2000 ).…”

Section: Discussionmentioning

confidence: 99%

“…8A and 8D did not show significant differences among all groups, which indicated that the loading history-induced changes in GJIC and protein expression of Cx43 in this study was not due to the phosphorylation of Ser368 of Cx43 by PKC. Mitogen-activated protein kinase (MAPK)-mediated phosphorylation of Cx43 at serine residues 255, 262, 279, and 282 was related to the Cx43 degradation ( Totland et al, 2020 ). Lots of studies showed that the MAPK pathway could be rapidly activated by various cellular mechanical stimuli ( Takano-Yamamoto, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Loading history changes the morphology and compressive force-induced expression of receptor activator of nuclear factor kappa B ligand/osteoprotegerin in MLO-Y4 osteocytes

Wang

Weng

Ishihara

et al. 2020

PeerJ

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Background In this study, we investigated the effect of the mechanical loading history on the expression of receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in MLO-Y4 osteocyte-like cells. Methods Three hours after MLO-Y4 osteocytes were seeded, a continuous compressive force (CCF) of 31 dynes/cm2 with or without additional CCF (32 dynes/cm2) was loaded onto the osteocytes. After 36 h, the additional CCF (loading history) was removed for a recovery period of 10 h. The expression of RANKL, OPG, RANKL/OPG ratio, cell numbers, viability and morphology were time-dependently examined at 0, 3, 6 and 10 h. Then, the same additional CCF was applied again for 1 h to all osteocytes with or without the gap junction inhibitor to examine the expression of RANKL, OPG, the RANKL/OPG ratio and other genes that essential to characterize the phenotype of MLO-Y4 cells. Fluorescence recovery after photobleaching technique was also applied to test the differences of gap-junctional intercellular communications (GJIC) among MLO-Y4 cells. Results The expression of RANKL and OPG by MLO-Y4 osteocytes without a loading history was dramatically decreased and increased, respectively, in response to the 1-h loading of additional weight. However, the expression of RANKL, OPG and the RANKL/OPG ratio were maintained at the same level as in the control group in the MLO-Y4 osteocytes with a loading history but without gap junction inhibitor treatment. Treatment of loading history significantly changed the capacity of GJIC and protein expression of connexin 43 (Cx43) but not the mRNA expression of Cx43. No significant difference was observed in the cell number or viability between the MLO-Y4 osteocyte-like cells with and without a loading history or among different time checkpoints during the recovery period. The cell morphology showed significant changes and was correlated with the expression of OPG, Gja1 and Dmp1 during the recovery period. Conclusion Our findings indicated that the compressive force-induced changes in the RANKL/OPG expression could be habituated within at least 11 h by 36-h CCF exposure. GJIC and cell morphology may play roles in response to loading history in MLO-Y4 osteocyte-like cells.

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“…The junctional membranes of the two adjacent cells are integrated into vesicle structures called annular gap junctions (Jordan et al 2001;Laird 2006). In line with these results, it has been shown that the reduction of ubiquitination of connexin proteins leads to a reduction in the gap junction turnover rate and their accumulation at the plasma membrane which is associated with a concomitant facilitation of intercellular communication (Totland et al 2020).…”

Section: Dynamics Of Gap Junctional Coupling and Uncouplingmentioning

confidence: 92%

Channels to consciousness: a possible role of gap junctions in consciousness

Dere

Zlomuzica²,

Dere

2020

Reviews in the Neurosciences

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The neurophysiological basis of consciousness is still unknown and one of the most challenging questions in the field of neuroscience and related disciplines. We propose that consciousness is characterized by the maintenance of mental representations of internal and external stimuli for the execution of cognitive operations. Consciousness cannot exist without working memory, and it is likely that consciousness and working memory share the same neural substrates. Here, we present a novel psychological and neurophysiological framework that explains the role of consciousness for cognition, adaptive behavior, and everyday life. A hypothetical architecture of consciousness is presented that is organized as a system of operation and storage units named platforms that are controlled by a consciousness center (central executive/online platform). Platforms maintain mental representations or contents, are entrusted with different executive functions, and operate at different levels of consciousness. The model includes conscious-mode central executive/online and mental time travel platforms and semiconscious steady-state and preconscious standby platforms. Mental representations or contents are represented by neural circuits and their support cells (astrocytes, oligodendrocytes, etc.) and become conscious when neural circuits reverberate, that is, fire sequentially and continuously with relative synchronicity. Reverberatory activity in neural circuits may be initiated and maintained by pacemaker cells/neural circuit pulsars, enhanced electronic coupling via gap junctions, and unapposed hemichannel opening. The central executive/online platform controls which mental representations or contents should become conscious by recruiting pacemaker cells/neural network pulsars, the opening of hemichannels, and promoting enhanced neural circuit coupling via gap junctions.

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Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications

Cited by 102 publications

References 164 publications

A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins

A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins

Loading history changes the morphology and compressive force-induced expression of receptor activator of nuclear factor kappa B ligand/osteoprotegerin in MLO-Y4 osteocytes

Channels to consciousness: a possible role of gap junctions in consciousness

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