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  • There is increasing evidence that Cxs in astrocytes


    There is increasing evidence that Cxs in astrocytes may play a role in several models of brain pathologies. Interestingly their roles are at the moment more considered through their hemichannel function (Bennett et al., 2012; Bosch and Kielian, 2014; Davidson et al., 2013; Orellana et al., 2016; Kim et al., 2016) than through gap junctional channel function. We think that this lack is in part due to the difficulty to have a simple experimental approach to determine the level of astroglial GJC in adult brain. Consequently, we consider that the Imeglimin synthesis of the gap-FRAP technique to acute brain slices from adult mice should now allow overpassing this technical obstacle. Indeed, the combination of approaches to assess hemichannel and gap junction channel functions of astroglial Cxs will contribute to fully investigate and understand their role in brain pathologies.
    Experimental procedure
    Acknowledgements The authors thank the animal facility staff of the Center of Interdisciplinary Research in Biology of the Collège de France and Pascal Ezan for technical help. Financial support was provided to CG by the Agence Nationale pour la Recherche grant NarConX 14-CE16-0022 and the Ligue Européenne Contre la Maladied’Alzheimer.
    Introduction Cell-cell communication is critical for all organ systems, and assured by transmembrane channels forming conductive pores in the plasma membranes between adjacent cells [1]. These channels located in so-called gap junctions (GJ) which consist of connexin (Cx) proteins [2], [3]. All human connexins have a common organization: four transmembrane domains separating two extracellular and one intracellular loop. Both the amino (NT) and carboxyl (CT) termini are intracellular [4]. Each transmembrane channel (hemichannel or connexon) is a hexamer of connexins, and connexons from one cell dock to hemichannels from an adjacent cell to form GJ channels [5]. GJs allow the diffusion of small (typically <1kDa) hydrophilic substances molecules and ions without exposure to the extracellular environment [6], [7]. GJs are the only channels which mediate direct cytoplasmic exchange - a process called gap junctional intercellular communication (GJIC) [8], [9], [10], [11], [12]. Interestingly, mutations in connexin genes, and therefore, in gap junctional communication, are associated with a large variety of pathologies and inherited connexin-associated disorders affect almost every major organ system [13], [14]. Of all 20 murine and 21 human connexins, Connexin 43 (Cx43, from the gene GJA1) is the most commonly expressed GJ protein [15], [16]. Cx43 has a fundamental role in excitable tissues to facilitate low resistance communication and thus rapid action potential transmission between adjacent cardiac cells. Such rapid communication synchronizes the cardiac heartbeat, and propagates electrical signals in the brain [17], [18], [19]. Cx43 is particularly enriched in ventricular cardiomyocytes where it is localized to the cardiomyocyte gap junction as part of the intercalated disc (ID) to facilitate action potential propagation [20]. In recent years, it has been reported that Cx43 can be involved in non-canonical events such as cell cycle regulation and cancer progression, wound healing, muscle differentiation, gene regulation and development [21], [22], [23], [24]. Cx43 protein, and in particular its C-terminus, has also been implicated in the trafficking of cardiac ion channels such as Nav1.5 and junctional protein N-cadherin [25], [26], [27], [28]. These studies identify Cx43 by immunohistochemistry with antibody epitopes at the C-terminus [25], or with a C-terminus truncation of the distal 5 amino acid residues [26], [27], or with co-immunoprecipitation with N-Cadherin [28]. Therefore, it is not a surprise that mutations or any deficiency in Cx43 expression or gap junction formation are associated with diverse pathologies, including heart disease [29], [30], [31], [32], [33], [34], [35], connective tissue disease [36], and cancer [21], [24]. Cardiac pathologies are frequently associated with connexin redistribution which is a form of gap junction remodeling [32], [37]. Moreover, impaired Cx43 trafficking contributes to the arrhythmias of sudden cardiac death [17], [30], [32], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49]. Decrease in expression and distribution of Cx43 in the cardiomyocytes has been described in the patients with hypertrophic cardiomyopathies [50], [51], [52], dilated cardiomyopathies [53], [54], ischemic cardiomyopathies [50], [52] and clinical congestive heart failure [33], and hereditary disorders Imeglimin synthesis [55]. Cx43 hemichannels and gap junctions have been implicated in mediating ischemia/reperfusion injury, cardioprotection and neuroprotection [56].