Chapter 5 │ Page 182 connexon opening to allow the entry of RONS to the cell interior. (3) Proposed mechanism to increase the intracellular RONS accumulation: Connexon blockers induce connexon close state and increase the intracellular accumulation of RONS, by entrance of them through the membrane and by natural intracellular production (e.g., within the mitochondria and cytoplasm). Taken together, these events induce cell death. Experimental reports have demonstrated that RONS can modulate GJs and connexons either via direct e ects on channel gating (pore opening/closing) [32] or by a ecting the intracellular tra icking of Cxs, impacting the number and stability of the GJ channel at the plasma membrane [143]. For instance, Ramachandran et al. demonstrated that H2O2-induced oxidative stress opens Cx43 proteins-composed connexons in fibroblastoid rat mammary tumor cell lines, via depolarization of the membrane potential. Consequently, the open connexons facilitated the entry of H2O2 in the cell interior to cause cell death, probably through apoptosis [32]. This result stresses an impressive property of the GJ channel under oxidation stress, where an open state can improve cancer cell death through a higher entrance of RONS to the cell interior (Figure 5.2). Lowering intracellular redox potential has also been suggested to increases the opening of Cx43 proteins-composed connexons. Retamal et al. transfected Cx43 proteins into HeLa cells to evaluate the e ect of reducing agents on dye uptake and connexon opening, and found that the redox molecule dithiothreitol increases the rate of dye uptake at the resting redox potential in cells expressing Cx43 proteins. Moreover, dithiothreitol increased the open probability of connexons at positive potentials. They found that the opening of connexons is regulated by the intracellular redox potential, which may act through the cysteine residues in the CT domain of Cx43 proteins [144]. Connexons can also be opened in Ca2+ ions deficient medium and dephosphorylation of critical residues [145,146]. Ca2+ signaling is strongly intertwined with RONS signaling, and both play crucial roles in cell death; the entry of extracellular Ca2+ into the cell promotes RONS production [147,148]. Thus, molecules that increase intracellular Ca2+ may induce connexon activation and
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