Fibroblast growth factors-5 and -9 distinctly regulate expression and function of the gap junction protein connexin43 in cultured astroglial cells from different brain regions

AbstractThe gap junction complex functions as a transport channel across the membrane. Among gap junction subunits, gap junction protein alpha 1 (GJA1) is the most commonly expressed subunit. However, the roles of GJA1 in the formation and function of cilia remain unknown. Here, we examined GJA1 functions during ciliogenesis in vertebrates. GJA1 was localized to the motile ciliary axonemes or pericentriolar material (PCM) around the primary cilium. GJA1 depletion caused the severe malformation of both primary cilium and motile cilia. Interestingly, GJA1 depletion caused strong delocalization of BBS4 from the PCM and basal body and distinct distribution as cytosolic puncta. Further, CP110 removal from the mother centriole was significantly reduced by GJA1 depletion. Importantly, Rab11, key regulator during ciliogenesis, was immunoprecipitated with GJA1 and GJA1 knockdown caused the mis-localization and mis-accumulation of Rab11. These findings suggest that GJA1 is necessary for proper ciliogenesis by regulating the Rab11 pathway.

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Involvement of the Gap Junction Protein, Connexin43, in the Formation and Function of Invadopodia in the Human U251 Glioblastoma Cell Line

Cells ◽

10.3390/cells9010117 ◽

2020 ◽

Vol 9 (1) ◽

pp. 117 ◽

Cited By ~ 3

Author(s):

Amandine Chepied ◽

Zeinaba Daoud-Omar ◽

Annie-Claire Meunier-Balandre ◽

Dale W. Laird ◽

Marc Mesnil ◽

...

Keyword(s):

Gap Junction ◽

Molecular Mechanisms ◽

Glioblastoma Cells ◽

Dynamic Interactions ◽

Cx43 Expression ◽

Junction Protein ◽

Gap Junction Protein ◽

And Function ◽

Low Cell Density ◽

Invadopodia Formation

The resistance of glioblastomas to treatments is mainly the consequence of their invasive capacities. Therefore, in order to better treat these tumors, it is important to understand the molecular mechanisms which are responsible for this behavior. Previous work suggested that gap junction proteins, the connexins, facilitate the aggressive nature of glioma cells. Here, we show that one of them—connexin43 (Cx43)—is implicated in the formation and function of invadopodia responsible for invasion capacity of U251 human glioblastoma cells. Immunofluorescent approaches—combined with confocal analyses—revealed that Cx43 was detected in all the formation stages of invadopodia exhibiting proteolytic activity. Clearly, Cx43 appeared to be localized in invadopodia at low cell density and less associated with the establishment of gap junctions. Accordingly, lower extracellular matrix degradation correlated with less mature invadopodia and MMP2 activity when Cx43 expression was decreased by shRNA strategies. Moreover, the kinetics of invadopodia formation could be dependent on Cx43 dynamic interactions with partners including Src and cortactin. Interestingly, it also appeared that invadopodia formation and MMP2 activity are dependent on Cx43 hemichannel activity. In conclusion, these results reveal that Cx43 might be involved in the formation and function of the invadopodia of U251 glioblastoma cells.

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Expression and function of the neuronal gap junction protein connexin 36 in developing mammalian retina

The Journal of Comparative Neurology ◽

10.1002/cne.20759 ◽

2005 ◽

Vol 493 (2) ◽

pp. 309-320 ◽

Cited By ~ 28

Author(s):

Kristi A. Hansen ◽

Christine L. Torborg ◽

Justin Elstrott ◽

Marla B. Feller

Keyword(s):

Gap Junction ◽

Connexin 36 ◽

Junction Protein ◽

Mammalian Retina ◽

Gap Junction Protein ◽

And Function

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Fibroblast Growth Factors as Tools in the Management of Neuropathic Pain Disorders

Current Drug Targets ◽

10.2174/1389450121666200423084205 ◽

2020 ◽

Vol 21 (10) ◽

pp. 1034-1043

Author(s):

Fatemeh Forouzanfar ◽

Hamid R. Sadeghnia

Keyword(s):

Neuropathic Pain ◽

Growth Factors ◽

Neural Development ◽

Drug Targets ◽

Fibroblast Growth Factors ◽

Large Family ◽

Fibroblast Growth ◽

And Function ◽

Somatosensory Nervous System ◽

The Relationship

Neuropathic pain is caused by a damage to or dysfunction of the somatosensory nervous system. The main mechanisms underlying neuropathic pain include ectopic activity in nociceptive nerves, peripheral and central sensitization, impaired inhibitory modulation, and microglial activation. Fibroblast growth factors (FGFs) make up a large family of growth factors that mediate neural development, metabolism, and function through three main key signaling pathways, including RAS/MAP kinase pathway, PI3 kinase/Akt pathway, and PLCγ. An association between the members of the FGF system and the improvement of neuropathic pain has become evident, recently. These signaling molecules may be expected to provide new drug targets for the treatment of neuropathic pain. To the best of our knowledge, it is the first study that reviews the relationship between some members of the FGF system and neuropathic pain.

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Amyloid-β regulates gap junction protein connexin 43 trafficking in cultured primary astrocytes

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013705 ◽

2020 ◽

Vol 295 (44) ◽

pp. 15097-15111

Author(s):

Mahua Maulik ◽

Lakshmy Vasan ◽

Abhishek Bose ◽

Saikat Dutta Chowdhury ◽

Neelanjana Sengupta ◽

...

Keyword(s):

Gap Junctions ◽

Gap Junction ◽

Connexin 43 ◽

Cx43 Expression ◽

Chemical Chaperone ◽

Junction Protein ◽

Gap Junction Coupling ◽

Gap Junction Protein ◽

Junction Coupling ◽

And Function

Altered expression and function of astroglial gap junction protein connexin 43 (Cx43) has increasingly been associated to neurotoxicity in Alzheimer disease (AD). Although earlier studies have examined the effect of increased β-amyloid (Aβ) on Cx43 expression and function leading to neuronal damage, underlying mechanisms by which Aβ modulates Cx43 in astrocytes remain elusive. Here, using mouse primary astrocyte cultures, we have examined the cellular processes by which Aβ can alter Cx43 gap junctions. We show that Aβ25-35 impairs functional gap junction coupling yet increases hemichannel activity. Interestingly, Aβ25-35 increased the intracellular pool of Cx43 with a parallel decrease in gap junction assembly at the surface. Intracellular Cx43 was found to be partly retained in the endoplasmic reticulum-associated cell compartments. However, forward trafficking of the newly synthesized Cx43 that already reached the Golgi was not affected in Aβ25-35-exposed astrocytes. Supporting this, treatment with 4-phenylbutyrate, a well-known chemical chaperone that improves trafficking of several transmembrane proteins, restored Aβ-induced impaired gap junction coupling between astrocytes. We further show that interruption of Cx43 endocytosis in Aβ25-35-exposed astrocytes resulted in their retention at the cell surface in the form of functional gap junctions indicating that Aβ25-35 causes rapid internalization of Cx43 gap junctions. Additionally, in silico molecular docking suggests that Aβ can bind favorably to Cx43. Our study thus provides novel insights into the cellular mechanisms by which Aβ modulates Cx43 function in astrocytes, the basic understanding of which is vital for the development of alternative therapeutic strategy targeting connexin channels in AD.

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