The Intercellular Synchronization of Ca2+ Oscillations Evaluates Cx36-Dependent Coupling

Bavamian, Sabine; Pontes, Helena; Cancela, José Antonio; Charollais, Anne; Startchik, Sergei; Ville, Dimitri Van De; Meda, Paolo

doi:10.1371/journal.pone.0041535

Cited by 14 publications

(23 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While upregulated GJ-signaling provides a logical starting point for the enhancement of beta cell connectivity, investigation of Cx36-modulating compounds has so far been complicated by their off-target effects. Notwithstanding, a recent study has described a panel of seventeen molecules that increase beta cell-beta cell communication, and further screening is warranted to validate their activity profiles and specificity [160]. In addition, atlases of both GPCR and paracrine factor expression/secretion have been reported for human and rodent islets [94,161], potentially accelerating the elucidation and development of putative candidates for manipulation of beta cell connectivity.…”

Section: Rescuing Beta Cell Connectivity During T2dmmentioning

confidence: 99%

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Rutter

Hodson

2014

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Beta cell connectivity describes the phenomenon whereby the islet context improves insulin secretion by providing a three-dimensional platform for intercellular signaling processes. Thus, the precise flow of information through homotypically interconnected beta cells leads to the large-scale organization of hormone release activities, influencing cell responses to glucose and other secretagogues. Although a phenomenon whose importance has arguably been underappreciated in islet biology until recently, a growing number of studies suggest that such cell-cell communication is a fundamental property of this micro-organ. Hence, connectivity may plausibly be targeted by both environmental and genetic factors in type 2 diabetes mellitus (T2DM) to perturb normal beta cell function and insulin release. Here, we review the mechanisms that contribute to beta cell connectivity, discuss how these may fail during T2DM, and examine approaches to restore insulin secretion by boosting cell communication.

show abstract

Section: Rescuing Beta Cell Connectivity During T2dmmentioning

confidence: 99%

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Rutter

Hodson

2014

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…In this scenario, innovative therapeutic approaches to interfere with the b-cell destruction in the context of T1D should benefit of the association of drugs restricting AMPK activation and of drugs promoting the expression and function of Cx36. The availability of novel methods for the screening of such specifically targeted drugs 43,48 will be instrumental to test this exciting possibility.…”

Section: Discussionmentioning

confidence: 99%

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

et al. 2013

View full text Add to dashboard Cite

Cell-to-cell communication mediated by gap junctions made of Connexin36 (Cx36) contributes to pancreatic b-cell function. We have recently demonstrated that Cx36 also supports b-cell survival by a still unclear mechanism. Using specific Cx36 siRNAs or adenoviral vectors, we now show that Cx36 downregulation promotes apoptosis in INS-1E cells exposed to the pro-inflammatory cytokines (IL-1b, TNF-a and IFN-c) involved at the onset of type 1 diabetes, whereas Cx36 overexpression protects against this effect. Cx36 overexpression also protects INS-1E cells against endoplasmic reticulum (ER) stress-mediated apoptosis, and alleviates the cytokine-induced production of reactive oxygen species, the depletion of the ER Ca 2 þ stores, the CHOP overexpression and the degradation of the anti-apoptotic protein Bcl-2 and Mcl-1. We further show that cytokines activate the AMP-dependent protein kinase (AMPK) in a NO-dependent and ER-stress-dependent manner and that AMPK inhibits Cx36 expression. Altogether, the data suggest that Cx36 is involved in Ca 2 þ homeostasis within the ER and that Cx36 expression is downregulated following ER stress and subsequent AMPK activation. As a result, cytokine-induced Cx36 downregulation elicits a positive feedback loop that amplifies ER stress and AMPK activation, leading to further Cx36 downregulation. The data reveal that Cx36 plays a central role in the oxidative stress and ER stress induced by cytokines and the subsequent regulation of AMPK activity, which in turn controls Cx36 expression and mitochondria-dependent apoptosis of insulin-producing cells.

show abstract

“…The identification of these drugs requires the development of new methods to rapidly and automatically screen many molecules for their effect on some bona fide connexindependent function (18). It will further require the investigation of the candidate drugs in vivo, under the conditions in which connexin signaling is integrated with, and likely interdependent on several other signaling mechanisms.…”

Section: G the Pharmacologymentioning

confidence: 99%

Connexins: Key Mediators of Endocrine Function

Bosco

Haefliger

Meda

2011

Physiological Reviews

Self Cite

158

185

View full text Add to dashboard Cite

The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their function. Some of these mechanisms depend on the intercellular diffusion of signal molecules in the extracellular spaces, whereas others require cell-to-cell contact. Among the latter mechanisms, those provided by the proteins of the connexin family are widespread in most tissues. Connexin signaling is achieved via direct exchanges of cytosolic molecules between adjacent cells at gap junctions, for cell-to-cell coupling, and possibly also involves the formation of membrane “hemi-channels,” for the extracellular release of cytosolic signals, direct interactions between connexins and other cell proteins, and coordinated influence on the expression of multiple genes. Connexin signaling appears to be an obligatory attribute of all multicellular exocrine and endocrine glands. Specifically, the experimental evidence we review here points to a direct participation of the Cx36 isoform in the function of the insulin-producing β-cells of the endocrine pancreas, and of the Cx40 isoform in the function of the renin-producing juxtaglomerular epithelioid cells of the kidney cortex.

show abstract

The Intercellular Synchronization of Ca2+ Oscillations Evaluates Cx36-Dependent Coupling

Cited by 14 publications

References 34 publications

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

Connexins: Key Mediators of Endocrine Function

Contact Info

Product

Resources

About