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  • The regulation of gap junction connexin


    The regulation of gap junction-connexin-mediated activities may be achieved through action on the channel gating properties (membrane voltage, pH, interaction with junctional and cytoskeletal proteins, Ca2+ and K+ concentrations, etc) or on the trafficking, turnover and localization of connexins. Short-term control of gap junction-connexin-mediated activities depends on posttranslational regulation of connexin molecules such as phosphorylation, ubiquitination or SUMOylation. Long-term control of gap junction-connexin-mediated activities depends on the up- or down-regulation of connexin levels, including trafficking, translocation, degradation and expression of connexins.
    Effects of toxicants on gap junctions Gap junctions, hemichannels and connexin molecules are involved in cellular interaction, proliferation, death, differentiation, migration and secretion [[50], [51], [52], [53], [54]]. Gap junctions, hemichannels and connexins are essential for tissue organization and thus are key sites for physiological regulation of tissue functioning. By interfering with individual steps in the gap junction-hemichannel-connexin life, metals, pharmaceuticals, and environmental toxicants may perturb the tissue/organ equilibrium [[55], [56], [57], [58], [59]]. Toxicants can directly impact on gap junction-mediated physiological events by affecting intercellular ion (Ca2+, H+) concentrations, the interaction of conenxins with other proteins, and the posttranslational and posttranscriptional modifications of the connexin proteins [[60], [61], [62]] or by altering gene transcription of connexins in an epigenetic manner like histone acetylation and DNA methylation [63]. During embryonic development, toxicants can induce mutations in connexin genes that result in the synthesis of non-functional connexins [45]. Some toxicant-induced pathologies are linked to abnormal connexin levels or localization, or to genetic mutations that cause a loss of function [59,64]. Studies have shown that certain compounds inducing cell transformation also affect gap junction-mediated intercellular communication [65].
    Gap junctions and connexin expression in the anterior pituitary Pioneer studies on gap junctions in the anterior pituitary reported gap junctions among lactotropes [66], among endocrine MK-8245 [67], between FS and endocrine cells, particularly lactotropes [68], among somatotropes [19] or solely among FS cells [14,15], Table 1. Fig. 1A, C and D show gap junctions joining endocrine cells, endocrine cell-FS cell as well as FS cells; these gap junctions are typically minute. The ability of anterior pituitary cells to communicate through gap junctions and the observation that cell-to-cell contacts influence cellular behaviour suggests that gap junction-mediated intercellular communication plays a role in pituitary physiology. In agreement with this view, blocking gap junctions affects Ca2+ wave propagation within somatotrope and FS cell networks [19,20]. Moreover, the number, distribution and localization of anterior pituitary gap junctions are regulated by hypothalamic, gonadal and adrenal cortex hormones and by other circulating hormones and factors [18,[69], [70], [71], [72], [73]]. Furthermore, the rat Cx43 promoter possesses an estrogen response element [74]. Therefore, toxicants with estrogenic or anti-androgenic effects or adrenocortical toxicity could compromise anterior pituitary cell communication which, in turn, may modify the activity of the cells (Table 2). Several connexins species have been reported in the anterior pituitary: Cx26 [75], Cx36 [76], Cx43 [77], Cx46 and Cx50 [78] (Table 1). However, Cx43 distribution shows discrepancies among reports. In rats, Yamamoto et al reported Cx43 in FS cells and gonadotropes [77] while other studies identified Cx43 among FS cells but not among somatotropes or gonadotropes [79]. Others studies observed Cx43 between FS and endocrine cells but not among endocrine cells [68,79]. Conversely, other reports localized Cx43 among endocrine cells [50]. In mink anterior pituitaries, Cx43 is mainly albeit not exclusively associated with FS cells [69]. Endocrine and FS cells express Cx46 [78] whereas Cx50 localizes to FS cells [78]. Cx43 and Cx50 are MK-8245 also associated with the wall of anterior pituitary blood vessels [69,78]. Fig. 1F, H and J illustrate Cx43, Cx46 and Cx50 individual distribution in anterior pituitary sections. Cx43 is preferentially associated with the cell membrane whereas Cx46 and Cx50 exhibit both membrane association and a spotty cytoplasmic distribution (Fig. 1F, H and J).