Gap-junction

Given the difficulty of obtaining three-dimensional crystals of membrane proteins, it is not surprising that the electron microscope technique is now widely used to study large membrane-bound complexes such as the acetylcholine receptor, rhodopsin, ion pumps, gap junctions, water channels and light-harvesting complexes, which crystallize in two dimensions. 

When cells lie adjacent to each other in animal tissues, they are often connected by gap junction structures, which permit the passive flow of small molecules from one cell to the other. Such junctions essentially connect the cells metabolically, providing a means of chemical transfer and communication. In certain tissues, such as heart muscle that is not innervated, gap junctions permit very large numbers of cells to act synchronously. Gap junctions also provide a means for transport of nutrients to cells disconnected from the circulatory system, such as the lens cells of the eye. 

Although gap junctions allow cells to communicate metabolically under normal conditions, the ability to close gap junctions provides the tissue with an important intercellular regulation mechanism. In addition, gap junctions provide a means to protect adjacent cells if one or more cells are damaged or... 

FIGURE 10.37 Gap Juoctioos consist of hexameric arrays of cylindrical protein subunits in the plasma membrane. The subunit cylinders are tilted with respect to the axis running through the center of the gap Junction. A gap Junction between cells is formed when two hexameric arrays of subunits in separate cells contact each other and form a pore through which cellular contents may pass. Gap Junctions close by means of a twisting, sliding motion in which the subunits decrease their tilt with respect to the central axis. Closure of the gap Junction is Ca -dependent. 

AQPO, formerly known as the Major Intrinsic Protein of 26 kDa (MDP26), is specifically expressed in the plasma membrane of eye lens fiber cells. It transports water to a low degree, but has also been implicated in cell adhesion and gap junction formation. Its main role is to maintain the transparency of the lens by maintaining a tight cellular connection to neighboring cells and/or by controlling the fluid circulation. 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Fransson-Steen R, Warngard L. 1992. Inhibitory effects of endosulfan on gap junctional intercellular communication in WB-F344 rat liver cells and primary rat hepatocytes. Carcinogenesis 13(4) 657-662. 

Kenne K, Fransson-Steen R, Honkasalo S, et al. 1994. Two inhibitors of gap junctional intercellular communication, TPA and endosulfan Different effects on phosphorylation of connexin 43 in the rat liver epithelial cell line, lAR 20. Carcinogenesis 15(6) 1161-1165. 

Musil LS et al. 1990. Differential phosphorylation of the gap junction protein connexin43 in junctional communication-competent and -deficient cell lines. J Cell Biol 111 2077-2088. 

Membranes are highly viscous, plastic structures. Plasma membranes form closed compartments around cellular protoplasm to separate one cell from another and thus permit cellular individuality. The plasma membrane has selective permeabilities and acts as a barrier, thereby maintaining differences in composition between the inside and outside of the cell. The selective permeabilities are provided mainly by channels and pumps for ions and substrates. The plasma membrane also exchanges material with the extracellular environment by exocytosis and endocytosis, and there are special areas of membrane strucmre—the gap junctions— through which adjacent cells exchange material. In addition, the plasma membrane plays key roles in cellcell interactions and in transmembrane signaling. 

There are regional asymmetries in membranes. Some, such as occur at the villous borders of mucosal cells, are almost macroscopicaUy visible. Others, such as those at gap junctions, tight junctions, and synapses, occupy much smaller regions of the membrane and generate correspondingly smaller local asymmetries. 

A state of fluidity and thus of translational mobitity in a membrane may be confined to certain regions of membranes under certain conditions. For example, protein-protein interactions may take place within the plane of the membrane, such that the integral proteins form a rigid matrix—in contrast to the more usual situation, where the hpid acts as the matrix. Such regions of rigid protein matrix can exist side by side in the same membrane with the usual lipid matrix. Gap junctions and tight junctions are clear examples of such side-by-side coexistence of different matrices. 

Whilst finite-element modelling of gap junctions occurs at a sub-cellular level, these models do not consider the operation of intact organs. Conversely, in models of the complete heart the discretisation is usually on a milhmetre scale. However, the cochlea (see Figure 9.3) is already being simulated on a 0.01 mm, or cellular, scale. Although cochlear malfunction is not hfe threatening, damage to it does adversely affect the ability of almost 1000000000 people to communicate. 

HABERMANN H, RAY V, HABERMANN w and PRiNS G s (2001) Alterations in gap junction protein expression in human benign prostatic hyperplasia and prostate cancer. J Urol 166(6) 2267-72. 

In the Unites States, the daily intake of 3-carotene is around 2 mg/day Several epidemiological studies have reported that consumption of carotenoid-rich foods is associated with reduced risks of certain chronic diseases such as cancers, cardiovascular disease, and age-related macular degeneration. These preventive effects of carotenoids may be related to their major function as vitamin A precursors and/or their actions as antioxidants, modulators of the immune response, and inducers of gap-junction communications. Not all carotenoids exert similar protective effects against specific diseases. By reason of the potential use of carotenoids as natural food colorants and/or for their health-promoting effects, research has focused on better understanding how they are absorbed by and metabolized in the human body. 

In atherosclerosis and other heart diseases, the role of carotenoids as antioxidants is probable, but for these types of diseases and also for other degenerative diseases such as cancers, non-antioxidant activities constitute other possible prevention mechanisms. These activities are, for example, stimulation of gap junction communications between cells, and the induction of detoxifying enzymes. The... 

Different types of apparently beneficial activities have been demonstrated in vitro for carotenoid oxidation products, including induction of gap-junctional communications, " growth inhibition of leukemia and cancer cells, induction of apoptosis... 

Another study showed that a mixture of oxidative metabolites of P-carotene, but not P-carotene, was able to increase the binding of benzo[a]pyrene to DNA. Other mixtures of P-carotene cleavage products have been shown to induce oxidative stress in vitro,exert cytotoxic and genotoxic effects, and inhibit gap junction intercellular communications. It has been suggested that these detrimental effects could possibly occur in vivo following the intake of high doses of carotenoids. 

Stahl, W. and Sies, H., Effects of carotenoids and retinoids on gap junctional communication, Biofactors, 15, 95, 2001. 

Yeh, S.L. and Hu, M.L., Oxidized [beta]-carotene inhibits gap junction intercellular communication in the human lung adenocarcinoma cell line A549, Food Chem. Toxicol., 41, 1677, 2003. 

Ozone attacks the rings of PAHs rather indiscriminately with fission of the rings to prodnce aldehyde gronps. There has been concern, however, since the products may be more harmful than their precursors. In the studies that are used as illustration, in vitro gap junctional intracellular communication (GJIC) was used to assess adverse alteration on the expression of genes at the transcription, translational, or posttranslational level ... 

The tight junction is a component of the junctional complexes which join cells. Immediately basolateral to the tight junction is the zonula adherens (Figs. 6 and 7). Because the zonula adherens and the gap junctions are focal contact regions, they do not impact transport by the paracellular pathway. All of these junctions are specialized regions of the lateral cell membrane which demarcate the lateral space. In certain types of cells the lateral space is rather narrow and... 

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