Connexon

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A connexon is an assembly of six connexin proteins, which forms a bridge called a gap junction between the cytoplasm of two adjacent cells. The connexon is actually the hemichannel; two connexons from opposing cells normally stick together to form the complete intercellular gap junction channel. However, in some cells, the hemichannel itself is active as a conduit between the cytoplasm and the extracellular space.

Structure

One connexon is made out of six connexin proteins. It is a hemichannel of a gap junction channel; one such channel needs two connexons. The various connexins can combine to each other, forming either homomeric (formed by only one protein type) or heteromeric (constituted by different connexins) hemichannels. Each of these hemichannels may have different functional properties including pore conductance, size selectivity, charge selectivity, voltage gating, and chemical gating. These hemichannels, in turn, can assemble into homotypic (consist of two identical) and heterotypic (consist of two different) gap junction channels.

The life cycle of connexon

A connexon is a short-lived protein structure, having the half-life of only a few hours [1, 2]. This provides a mean for accurate gap-junction protein regulation, since gap-junction protein can be changed rapidly, depending on external conditions.

Connexons are synthesised in the endoplasmic reticulum (ER) or ER/Golgi intermediate place. The place may differ between connexins and even cell types [3]. This process is generally completed by the arrival of the connexons in the Golgi apparatus.

Connexins do not possess a signal peptide sequence, which usually shows peptide destination place. Trafficking of connexins to the plasma membrane requires their oligomerisation into connexons. Then connexon hemichannels are carried from the Golgi to the plasma membrane by small vesicles, bigger than 0.5 mikcometers in diameter [3]. Under normal conditions, connexons are carried in a closed configuration, interacting with microtubules. Insertion of connexons into the plasma membrane occurs over large area of the cell’s surface. Once inserted into the plasma membrane, hemichannels diffuse laterally and tie up with counterparts contributed by a neighbouring cell to form functional gap junction. Gap junctions tend to interact to generate plagues. Clustering of connexins require a wide variety of other protein, like calmodulins [3], aquaporins [4], cytoplasmic proteins [5] and cytoskeletal proteins [6].

Turnover of connexons from the plasma membrane usually is a rapid process, determining the lifetime of connexons. Under conditions of stress, gap junction removal is even more accelerated. The process occurs mainly by phagocytosis from the centre of a plaque of connexons. Large endocytic vesicles, containing annular gap junctions, are formed and targeted to the lysosomes where they are degradated. Thus connexon assembly is a dynamic process as new channels are continuously added to the edge of the gap junction clusters and older paired connexons are removed from its centre.

Hemichannels

For several decades, hemichannels found at nonjunctional membranes were thought to remain permanently closed to avoid cell death. Once opened, they could lead to the cell death. Recently there are data, reporting the existence of regulative hemichannels, which could be opened and closed in cultured cells.

Opening of hemichannels formed by different connexin types is rather rear or absent under resting conditions but can be enhanced by several factors. Low extracellular calcium, mechanical stimulation and various agonists can enhance the opening of hemichannels. Traditional gap junction blockers, hyperpolarisation of the plasma membrane, extracellular acidification and some ions or molecules could close hemichannels.

The unitary conductance determined for some homomeric connexin hemichannels ranges from 31 to 352 pS [7, 8]. Hemichannels are permeable to small molecules (e.g., NAD+, ATP and inositol trisphosphate) and to some experimental cell dyes. Nevertheless, it is still not known whether cell surface hemichannels have different permeability properties than connexons formed by the same connexin type. It is unknown whether physiological stimuli may regulate hemichannel openings that allow communication between the intracellular and extracellular compartments.

There are several proposals for hemichannels function. They may regulate the cell volume in response to changes in extracellular calcium concentration [9]. In addition, Cx43 hemichannels mediate the release of NAD+ to the extracellular medium in fibroblasts [10]. Mechanical stimulation elicits release of ATP through Cx43 hemichannels in astrocytes and could mediate the propagation of calcium signals for intercellular communication in astrocytes and other nonexcitable cells [11]. It has been proposed that opening of Cx26 hemichannels could depolarize retinal horizontal cells and therefore release glutamate from cones [12]. Massive opening of Cx43 hemichannels has been demonstrated in astrocytes and cardiomyocytes while mimicking ischemia [13]. Therefore it would speed up mechanisms leading to cell death.

See also

References

1. Crow DS, Beyer EC, Paul DL, Kobe SS, and Lau AF. (1990). Phosphorylation of connexin43 gap junction protein in uninfected and Rous sarcoma virus-transformed mammalian fibroblasts. Mol Cell Biol 10: 1754–1763.

2. Fallon RF and Goodenough DA. (1981). Five hour half-life of mouse liver gap junction protein. J Cell Biol 90: 521–526.

3. Martin PE and Evans WH. (2004). Incorporation of connexins into plasma membranes and gap junctions. Cardiovasc Res. 62(2): 378-387.

4. Rash JE and Yasumura T. (1999). Direct immunogold labeling of connexins and aquaporin-4 in freeze-fracture replicas of liver, brain, and spinal cord: factors limiting quantitative analysis. Cell Tissue Res 296: 307–321.

5. Sotkis A, Wang XG, Yasumura T, Peracchia LL, Persechini A, Rash JE, and Peracchia C. (2001).Calmodulin colocalizes with connexins and plays a direct role in gap junction channel gating. Cell Commun Adhes 8: 277–281.

6. Giepmans BN, Verlaan I, Hengeveld T, Janssen H, Calafat J, Falk MM, and Moolenar WH. (2001).Gap junction protein connexin-43 interacts directly with microtubules. Curr Biol 11: 1364–1368.

7. Ebihara L, Xu X, Oberti C, Beyer EC, and Berthoud VM. (1999). Co-expression of lens fiber connexins modifies hemi-gap-junctional channel behavior. Biophys J 76: 198–206.

8. Eskandari S, Zampighi GA, Leung DE, Wright EM, and Loo DD. (2002). Inhibition of gap junction hemichannels by chloride channel blockers. J Membr Biol 185: 93–102.

9. Quist AP, Rhee SK, Lin H, and Lal R. (2000). Physiological role of gap-junctional hemichannels. Extracellular calcium-dependent isosmotic volume regulation. J Cell Biol 148: 1063–1074.

10. Bruzzone S, Franco L, Guida L, Zocchi E, Contini P, Bisso A, Usai C, and De Flora A. (2001). A self-restricted CD38-connexin 43 cross-talk affects NAD_ and cyclic ADP-ribose metabolism and regulates intracellular calcium in 3T3 fibroblasts. J Biol Chem 276: 48300–48308.

11. Stout CE, Costantin JL, Naus CC, and Charles AC. (2002). Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277: 10482–10488.

12. Kamermans M, Fahrenfort I, Schultz K, Janssen-Bienhold U, Sjoerdsma T, and Weiler R. (2001). Hemichannel-mediated inhibition in the outer retina. Science 292: 1178–1180.

13. Contreras JE, Sa´nchez HA, Eugenı´n EA, Speidel D, Theis M, Willecke K, Bukauskas FF, Bennett MVL, and Sa´ez JC. (2002). Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc Natl Acad Sci USA 99: 495–500.