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Advanced Biochemistry CHM486A
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Instructor: Dr Matthew Saderholm

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Connexin 43: A Transmembrane Protein


Gap Junctions
           Connexin 43 is the most common gap junction protein within the body. A Gap junction protein allows for continuity of cytoplasm between adjacent cells. Because of their importance in intercellular communication gap junction proteins are present throughout the body, particularly within bone (1) and eye cells (2). Many Connexins are expressed in a tissue specific manner, but Connexin 43 is everywhere ( 3). Because of their placement throughout the body, connexins have many roles, such as their pivotal role in the process of healing wounds and during development (2). Because of a similar function, all 20+ connexins with the connexin superfamily share a common architecture (1). This structure entails: four hydrophobic amino acid regions that span the membrane, two extracellular loops, and three cytoplasmic components (2). A gap junction channel is composed of two end-to-end connexon molecules that originate from different connected cells, see Figure 1 (4). Since a gap junction is composed of two connexons, they can be either homo or hetero. Connexin 43 is notable, in that it will function in a hetero connexon, and can often take on the characteristics of other connexin varieties (1). Each of these connexons is made up of six connexin proteins, as shown in Figure 1 (2).


          Figure 1. This figures shows a gap junction within the membrane of two adjacent cells. This cross section also shows a how the connexon is composed of 6 connexins (2).

          The signal that causes the 6 connexin to form a connexon seems to originate from within the connexin polypeptide(5). The binding is head-to-head and occurs by way of non-covalent interactions between the extracellular loops of apposing connexins (5). Each of these loops possesses three conserved cystein residues that form disulphide bridges, see the Amino Acid button in Jmol with the cystein being yellowish in color(5). Studies have suggested this causes the formation of a beta structure that maybe similar to a beta barrel (5). The two hemichannels that compose a junctional channel are staggered by roughly 30 degrees relative to each other so that the alpha helices of each connexin monomer are axially aligned with the alpha helices of the two adjacent monomers in the opposing hemichannel (5).

          It's the different combination of connexins that defines the specific function of the connexon (3). Its function is to allow two way movement of intercellular ions, metabolites, and secondary messengers (2). All cells can form a function gap junction with neighboring cells if connexins are present in both cells (3). It is this communication that allows for the propagation of cell death, following injury, as well as the survival-modulating signals for the surrounding cells (2). This structure allows for the transfer of small molecules such as cAMP, Ca2+, K+, and other signal molecules that are smaller than about 1kDa in size (2). Gap junction channels tend to be aggregated together in areas where the adjacent membrane is running parallel (2). The gap junction tends to get its name from the 2 nm gap between the two membranes (2).

Specifically Connexin 43
           The specific role of the gap junction Cx43 is to contribute to local metabolic homeostasis and synchronization of cellular activities by allowing bidirectional, intercellular movement of ions, metabolites and second messengers (2). Connexin 43 is the predominant connexin isoform in a number of cell types, ranging from vascular cells, to neural progenitor cells, and even gastrointestinal cells (4). Connexin 43 was first found in heart muscle cells (3). Connexin 43 gap junctions are responsible for controlling the synchronous heart muscle contraction (3). It is able to do this by diffusion (5). While this doesn't undergo active transport, the rate of diffusion is estimate at 1 to 2 times greater than what would be expected from passive diffusion (5). This rate suggests a slight affinity for the channel to be occupied (5). Of all the connexin, Cx43 has the widest pore, with a minimum diameter of 15 angstroms (4). Cx43 is the most selective of anions, with a selectivity ration of 1.17 anion-to-cation (4). Connexin 43 is instilled into connexons, while inside the trans-Golgi network (2). From there it moves along the microtubule-dependent pathways to an area on the cell surface that has other gap junctions (2). From synthesis to degradation, Connexin 43 has a half-life of only 1-3 hours, before being digested (2).

Cx43's specific roles within the body:
          In this section each paragraph will discuss Connexin 43's affects on one specific area within the body.

           Skeleton: Connexin plays a vital role in skeletal structure because of the need for communication between cells that are changing to specific need. Gap junctions are prevalent throughout the skeletal system, especially in osteoblasts and osteocytes (1). Osteoblasts are single nucleus cells that are responsible for bone formation; while ostecytes are calcified osteoblasts whose function is sending signals for functional osteoblasts (6). Connexin 43 is the most prevalent connexin within the skeletal system. Due to its prevalence, its function is understood thanks to human and mouse models. Growing research suggests Connexin 43 contributes to the bone cells response to hormonal stimulation (1).

           Skin: Connexin 43 has been identified within the epidermis and dermis. Its primary role is in wound healing and during development (2). Connexin 43 knockdown causes a reduction of swelling and inflammation (2). When applied to a wound within a gel, it caused improved healing, as well as a reduction in scar tissue after healing (2).

           Eye: At least 10 different Connexins have been found within the mammalian eye (2). When located within the lens, its primary function is communication with the epithelial layer. During development, as well as adulthood, Connexin 43 plays a significant role in regulation nutrient and waste transport (2).

           Central Nervous System: Connexin 43 is the most common connexin with in the central nervous system (2). Its primary role is maintaining the blood-brain barrier, as well as within astrocytes that surround chemical synapses (2).


Malfunctions
           For its prevalence and many functions that Connexin 43 helps control and regulate there is only one disease associated with its mutation, ODDD or ocudentodigital dysplasia (2). Figure 2 displays where possible mutations may disrupt the function. It is a relatively rare disorder that only affects several hundred persons worldwide (2). Persons with this disease usually have symptoms such as eye and cardiac abnormalities, thin nose, the little finger being held in a flexed position, as well as a number of others (2).


           Figure 2. Shows the gapjunction from a top veiw. The connexin alpha helices are shown in yellow, with the red dots symbolizing possible connexin mutations that would impair the function (7 ).

           In conclusion, Connexins are a vital transmembrane protein that help to build gap junctions. They do this by combining 6 connexins to form a connexon, or half of the cellular pathway. Since gap junctions allow for intercellular communication, they play a vital role in cellular life. As the most common Connexin, Connexin 43 has a large impact in the skeletal system, skin, eye, CNS, as well as other regions. Due to the importance of Connexin 43, it is highly conserved and thus rare.






References

1. Civitelli, R. (2008) Cell-cell Communication in the Osteoblast/Osteocyte Lineage, Biochem. Biophys. Acta., 473, 188-192.

2. Danesh-Meyer, H.V., and Green, C.R. (2008) Focus on Molecules: Connexin 43: Mind the gap, J. Exp. Eye Res., 20, 1-2.

3. Rodriguez-Sinovas, A., Cabestrero, A., Lopez, D., Torre, I., Morente, M., Abellan, A., Miro. E., Ruiz-Meana, M., and Garcia-Dorado, D. (2007) The Modulatory Effects of Connexin 43 on Cell Death/Survival Beyond Cell Coupling, J. Prog. Biophys. Molec. Bio., 94, 219-232.

4. Neijssen, J., Pang, B., and Neefjes, J. (2007) Gap Junction-Mediated Intercellular Communication in the Immune System, J. Prog. Biophys. Molec. Bio., 94, 207-218.

5. Herve, J., Bourmeyster, N., Sarrouilhe, D., Duffy, H. (2007) Gap Junctional Complexes: From Partners to Functions, J. Prog. Biophys. Molec. Bio., 94, 29-65.

6. Sosinsky, G.E., Nicholson, B.J. (2005) Structural Organization of Gap Junction Channels, Biochim. Biophy. Acta., 1711, 99 - 125.

7. Noble, B. (2008) The Osteocyte Lineage, Biochem. Biophys. Acta. 473, 106-111

8. Yeager, M., and Harris, A. (2007) Gap Junction Channel Structure in the Early 21st Century: Facts and Fantasies, J. Curr. Opin. Cell Bio., 19, 521-528.