Diversity in connexin biology

Lucaciu, Sergiu A.; Leighton, Stephanie E.; Hauser, Alexandra; Yee, Ryan; Laird, Dale W.

doi:10.1016/j.jbc.2023.105263

Cited by 23 publications

(10 citation statements)

References 191 publications

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“…Moreover, in 2D cultures a considerable number of cells or cell clusters did not respond in terms of measurable electrical activity upon increases of glucose. We therefore tested whether an increase in the expression of CX36, required for intercellular coupling and participating in adhesion (51), may improve their electrical responses.…”

Section: Rat Ins-1 Cell Spheroidsmentioning

confidence: 99%

Extracellular electrophysiology on clonal human β-cell spheroids

Puginier,

Fischer,

Gaitan

et al. 2024

Preprint

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Pancreatic islets are important in nutrient homeostasis and improved cellular models of clonal origin may very useful especially in view of relatively scarce primary material. Close 3D contact and coupling between beta-cells are a hallmark of physiological function improving signal/noise ratios. Extracellular electrophysiology using micro-electrode arrays (MEA) is technically far more accessible than single cell patch clamp, enables dynamic monitoring of electrical activity in 3D organoids and recorded multicellular slow potentials (SP) provide unbiased insight in cell-cell coupling. We have therefore asked whether 3D spheroids enhance clonal beta-cell function such as electrical activity and hormone secretion using human EndoC- betaH1, EndoC- betaH5 and rodent INS-1 cells. EndoC- betaH1 spheroids exhibited increased signals in terms of SP frequency and especially amplitude as compared to monolayers and even single cell action potentials (AP) were quantifiable. Enhanced electrical signature in spheroids was accompanied by an increase in the glucose stimulated insulin secretion index. EndoC- betaH5 monolayers and spheroids gave electrophysiological profiles similar to EndoC- betaH1, except for a higher electrical activity at 3 mM glucose, and exhibited moreover a biphasic profile. Again, physiological concentrations of GLP-1 increased AP frequency. Spheroids also exhibited a higher secretion index. INS-1 cells did not form stable spheroids, but overexpression of connexin 36, required for cell-cell coupling, increased glucose responsiveness, dampened basal activity and consequently augmented the stimulation index. In conclusion, spheroid formation enhances physiological function of the human clonal beta-cell lines and these models may provide surrogates for primary islets in extracellular electrophysiology.

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Section: Rat Ins-1 Cell Spheroidsmentioning

confidence: 99%

Extracellular electrophysiology on clonal human β-cell spheroids

Puginier,

Fischer,

Gaitan

et al. 2024

Preprint

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“…The human genome contains 21 Gap Junction proteins (also known as connexins) They are divided by sequence similarity into five subgroups labelled as GJAP's through GJEP's or with the corresponding Greek letters, α through ε. Figure 5 shows a phylogram of these proteins: (See also [12,13] for fuller discussions of the evolution and biology of the Gap Junction proteins). Seven of the gap junction proteins are found in Table S1 of the Orthologs at the base of the Olfactores, and these are labelled accordingly in the figure.…”

Section: The Gap Junction Proteinsmentioning

confidence: 99%

“…Among many other roles in the body, gap junction proteins are found in the Schwann cells, whose development in evolution required, as we have seen, the tunicates' invention of the first gap junction proteins. These Schwann cells form a sheath that wraps around a neuron and provides the insulating myelin coating to the nerves of (See also [12,13] for fuller discussions of the evolution and biology of the Gap Junction proteins). Seven of the gap junction proteins are found in Table S1 of the Orthologs at the base of the Olfactores, and these are labelled accordingly in the figure.…”

Section: The Gap Junction Proteinsmentioning

confidence: 99%

Orthologs at the Base of the Olfactores Clade

Stein

2024

Genes

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Tunicate orthologs in the human genome comprise just 84 genes of the 19,872 protein-coding genes and 23 of the 16,528 non-coding genes, yet they stand at the base of the Olfactores clade, which radiated to generate thousands of tunicate and vertebrate species. What were the powerful drivers among these genes that enabled this process? Many of these orthologs are present in gene families. We discuss the biological role of each family and the orthologs’ quantitative contribution to the family. Most important was the evolution of a second type of cadherin. This, a Type II cadherin, had the property of detaching the cell containing that cadherin from cells that expressed the Type I class. The set of such Type II cadherins could now detach and move away from their Type I neighbours, a process which would eventually evolve into the formation of the neural crest, “the fourth germ layer”, providing a wide range of possibilities for further evolutionary invention. A second important contribution were key additions to the broad development of the muscle and nerve protein and visual perception toolkits. These developments in mobility and vision provided the basis for the development of the efficient predatory capabilities of the Vertebrata.

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“…Gap junctions are specialized transmembrane channels composed of connexin proteins that canonically function to facilitate the direct intercellular exchange of small molecules, ions and metabolites in a process called gap junctional intercellular communication (GJIC) ( Zhou et al, 2023 ; Laird and Lampe, 2022 ; Lucaciu et al, 2023b ). The scope of potential transjunctional molecules involved in GJIC is enormous and includes common signaling molecules, such as ATP, AMP, inositol trisphosphate and Ca 2+ ( Leybaert et al, 2017 ; Mese et al, 2007 ; Harris, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

“…Although cells generally express two or more different connexins, channel complexity is thought to be enhanced in the epidermis with human and rodent keratinocytes differentially expressing numerous distinct isoforms (Cx26, Cx30, Cx30.3, Cx31, Cx31.1, Cx32, Cx37, Cx40, Cx43, and Cx45; designated in the current study as ‘keratinocyte connexins’) ( Di et al, 2001 ; Faniku et al, 2015 ; Goliger and Paul, 1994 ). Consequently, keratinocyte connexins oligomerize into homomeric or heteromeric connexons en route to the plasma membrane, where they proceed to form homotypic or heterotypic channels that can exhibit distinct permeabilities and biophysical properties, which uniquely contribute to the maintenance of epidermal homeostasis and physiological function through GJIC ( Lucaciu et al, 2023b ; Martin et al, 2014 ; Scott et al, 2012 ; Martin and van Steensel, 2015 ; Koval et al, 2014 ). However, several reports suggest that Cx31.1 (encoded by GJB5 ) fails to assemble into functional gap junction channels in Xenopus oocytes and HeLa cells, but it is not known whether this is the case in connexin-rich keratinocytes where Cx31.1 is endogenously expressed in mammals and, in some cases, seen as puncta at the cell membrane ( Hennemann et al, 1992 ; Bruzzone et al, 1994 ; Manthey et al, 1999 ; Manthey et al, 2001 ; Harris, 2001 ; Nugent et al, 2021 ; Goliger and Paul, 1994 ; Di et al, 2001 ; Chang et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Cx31.1 can selectively intermix with co-expressed connexins to facilitate its assembly into gap junctions

Leighton,

Wong,

Lucaciu

et al. 2024

Journal of Cell Science

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Connexins are channel forming proteins that function to facilitate gap junctional intercellular communication. Here we use dual cell voltage clamp and dye transfer studies to corroborate past findings that Cx31.1 is defective in gap junction channel formation; illustrating that Cx31.1 alone does not form functional gap junction channels in connexin-deficient cells. Rather Cx31.1 transiently localizes to the secretory pathway with a subpopulation reaching the cell surface which is rarely seen in puncta reminiscent of gap junctions. Intracellular retained Cx31.1 was subject to degradation as Cx31.1 accumulated in the presence of proteasomal inhibition, had a faster turnover when Cx43 was present, and ultimately reached lysosomes. While intracellularly retained Cx31.1 was found to interact with Cx43, this interaction did not rescue its delivery to the cell surface. Conversely, the co-expression of Cx31 dramatically rescued the assembly of Cx31.1 into gap junctions where gap junction-mediated dye transfer was enhanced. Collectively, our results indicate that the localization and functional status of Cx31.1 is altered through selective interplay with co-expressed connexins, perhaps suggesting Cx31.1 is a key regulator of intercellular signalling in keratinocytes.

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Diversity in connexin biology

Cited by 23 publications

References 191 publications

Extracellular electrophysiology on clonal human β-cell spheroids

Extracellular electrophysiology on clonal human β-cell spheroids

Orthologs at the Base of the Olfactores Clade

Cx31.1 can selectively intermix with co-expressed connexins to facilitate its assembly into gap junctions

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