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  • br Conclusions There are a number of


    Conclusions There are a number of factors that affect the transit of solutes through gap junction channels. Fig. 4 provides a simplified illustration of those factors. First is the cytoplasmic vestibule through which all permeable solutes must pass to gain access to the pore. In an equivalent circuit it represents access resistance. The vestibule might best be viewed as the site or sites that allow for charge and size discrimination either through binding or electrostatic interactions. Both Cx37 and Cx43 have been shown to possess fixed charge moieties within the vestibule. Both variation of ionic strength and voltage dependence can be used to assess the presence of fixed charges [20], [50]. The second factor is the narrowest diameter along the length of a given pore, functioning as a size selectivity point. For example Cx26 has its narrowest diameter at the cytoplasmic mouth of the pore that opens into the cytoplasmic vestibule, which inherently determines solute transit [11]. A third factor within the pore that affects the transit of solutes is hydrogen bonding. Both experimental data and simulations suggest that solute permeation is highly dependent on the energy of hydration [24], [39]. If energy of hydration is a dominating factor governing permeation of solutes, then the more hydrogen bonding there is, the lower the permeability. For solutes, both solute hydrogen bonding to the pore wall moieties and the solvent within the pore itself would then be one of the rate limiting steps for permeation. A fourth factor, also within the pore, is potential Dihydroeponemycin mg for solutes to interact with. Again, both experimental data and simulations suggest this a factor within the pore, albeit a lesser one than hydrogen bonding [24], [39]. Oligonucleotide permeability is clearly of great importance when considering that microRNAs/siRNAs could act as intercellular second messengers regulating gene expression. Oligonucleotides are only weakly positively charged molecules and more subject to hindered access due to their length than similarly charged smaller spheroid molecules. The oligonucleotide must, in essence, “line up” in order to gain access. Once so aligned, the oligonucleotide would most likely have a greater interaction with the pore wall via hydrogen bonding. Whether such interactions would promote or hinder transit is not clear from experimental data, but the simulation of Luo et al. [39] applied to an oligonucleotide might well lend valuable insight. The physiological role of ionic flux through gap junctions in the heart was clearly demonstrated by Barr et al. [51] who used a sucrose gap method to increase the extracellular longitudinal resistance in a cardiac bundle. As the resistance increased, conduction slowed and then finally failed. A similar conclusion has been drawn concerning the vasculature with regard to endothelium-dependent smooth muscle hyperpolarization [52]. For second messengers, an in vivo demonstration has been more elusive as many of the second messengers, including cAMP, are not only permeable to gap junction channels [33] but can also affect connexin expression [1], [53], [54]. Despite this complication, determination of accurate permeability values for specific intercellular messengers like cAMP has been deemed essential to ultimately answering the question of physiological relevance [55], [56]. The evidence for intercellular siRNA/micoRNA transit that is able to affect gene expression has been shown in vitro [19], [41], [45], [46], [47], [48], but an in vivo demonstration has yet to be validated.
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    Acknowledgments This work was supported by the National Institutes of Health grant GM088181 to V.V.
    Introduction Major depressive disorder is a common mental disease, affecting an increasing proportion of the world's population. Although the pathology of major depressive disorder has been studied for decades, little is known about its underlying mechanism, limiting current treatments (Belmaker and Agam, 2008, Krishnan and Nestler, 2008). Growing evidence has suggested key roles for gap junctions in depression. Gap junctions directly contact adjacent cells, allowing for the diffusion of small molecules ions, amino acids, nucleotides, and second messengers (Alexander and Goldberg, 2003). Dysfunction of gap junctions in the prefrontal cortex induces depressive-like behaviors in rats (Sun et al., 2012). Connexin43 (Cx43), a major component of gap junctional channels, is mostly synthesized by astrocytes in the brain (Nagy et al., 2004). Expression of Cx43 protein in astrocytes is downregulated in patients with major depressive disorder and in suicide completers (Bernard et al., 2011, Ernst et al., 2011). Therefore, changes in gap junctions in astrocytes may play an important role in the pathology of major depressive disorder.