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Chapter 5 │ Page 167 Cx26/Cx32 proteins-composed GJs (Cx26/Cx32-GJs) are more sensitive to Vj than to Vi‒o [63]. These changes in electrical properties suggest that there are di erences between the molecular conformations of connexons that depend on the Cx typecomposed connexons. Interestingly, changes on GJs electrical properties have been linked to pathological conditions [64]. The GJ is stabilized by non-covalent interactions via H-bonds between EL-1 and EL2 of their Cxs, which are responsible for docking processes [65,66], while the NT domain participates in the oligomerization, tra icking, and channel gating of Cxs [67,68]. The CL and CT domains are responsible for specific channel properties of di erent Cxs, including unitary conductance, pH and voltage dependence, and selective permeability to small molecules (< ~ 1.2 kDa) [69,70] (Figure 3d). In addition, the CT domain plays a role in the phosphorylation of some Cxs (e.g. Cx43 and Cx47 proteins) [71,72] and regulates intercellular Ca2+ flow [73,74], cell growth, and cell mobility. Recently, Ray and Mehta demonstrated experimentally the importance of the two CT cysteine residues of Cx32 proteins in regulating the tra icking and stability of Cx32 proteins from the endoplasmic reticulum to the Golgi apparatus, and hence its ability to assemble into GJs [75]. Structural, electrical and dynamic properties of GJs channel can facilitate the exchange of various molecules such as RONS, ions, and di erent cytokines between adjacent cells [29-31] (Figure 3d), but these properties can be altered during malignant cellular transformations. 3. PRO-TUMORIGENIC PROPERTIES OF Cxs AND GJs An increasing body of experimental work has demonstrated the protumorigenic properties of Cxs and GJs in normal and cancer cells (Figure 1a). Several Cx subtypes (e.g. Cx26, Cx32, and Cx43) are linked to malignant transformation and tumor progression, mainly in the advanced cancer stages. Increased expression of Cx26 proteins was found in lung squamous cell

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