Connexin

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An open gap junction, comprised of 6 connexins.
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An open gap junction, comprised of 6 connexins.

Connexins, or gap junction proteins, are a family of structurally-related transmembrane proteins that compose vertebrate gap junctions. (An entirely different family of proteins, the innexins forms gap junctions in invertebrates). [1] Each gap junction is formed from 2 hemichannels, which are each composed of 6 connexin molecules. Gap junctions, and thus connexins, are essential for many physiological processes such as the coordinated depolarization of cardiac muscle. For this reason, the mutation of connexin-encoding genes can lead to functional or developmental abnormalities.


Contents

[edit] Structure

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Connexins are four-pass transmembrane proteins with both C and N cytoplasmic termini, a cytoplasmic loop (CL) and two extra-cellular loops, (EL-1) and (EL-2). Connexins are assembled together in groups of 6 to form hemichannels, or connexons. Two hemichannels then combine to form a gap junction. The connexin gene family is diverse, with 20 identified members in the sequenced human genome. They usually weigh between 26 and 60 kDa, and contain about 380 amino acids in length, though this varies from type to type. Different connexin gene products combine to form gap junctions with different properties, including pore conductance, size selectivity, charge selectivity, voltage gating properties, and chemical gating properties.

[edit] Nomenclature

In recent literature, connexins are most commonly named according to their molecular weights, e.g. Cx26 is the connexin protein of 26 kDa. This leads to confusion when connexin genes from different species are compared, e.g. human Cx36 is homologous to zebrafish Cx35. There was also an earlier classification of connexins according to functional properties, e.g. Cx-α1, etc.

[edit] Biosynthesis and Internalization

A remarkable aspect of connexins is that they have a relatively short half life of only a few hours. [2] The result is the presence of a dynamic cycle by which connexins are synthesized and replaced. It has been suggested that this short life span allows for more finely regulated physiological processes to take place, such as in the myometrium.

[edit] From the Nucleus to the Membrane

As they are being translated by ribosomes, connexins are inserted into the membrane of the endoplasmic reticulum (ER) (Bennett and Zukin, 2004). It is in the ER that connexins are properly folded, yielding two extracellular loops, EL-1 and EL-2. It is also in the ER that the oligomerization of connexin molecules into hemichannels begins, a process which may continue in the UR-Golgi intermediate compartment as well.[3] The arrangements of these hemichannels can be homotypic, heterotypic, and combined heterotypic/heteromeric.

After exciting the ER and passing through the ERGIC, the folded connexins will usually enter the cis-Golgi network. [4] However, some connexins, such as Cx26 may be transported independent of the Golgi. [5][6][7] [8] [9]

[edit] Gap Junction Assembly

After being inserted into the plasma membrane of the cell, the hemichannels freely diffuse within the lipid bilayer. [10] Through the aid of specific proteins, mainly cadherins, the hemichannels are able to dock with hemichannels of adjacent cells forming gap junctions. [11] Recent studies have shown the existence of communication between adherens junctions and gap junctions[12], suggesting a higher level of coordination than previously thought.

[edit] Function

Connexin gap junctions are found only in vertebrates. A functionally analogous but genetically unrelated group of proteins, the pannexins are expressed in both vertebrate and invertebrate species. The innexin proteins, invertebrate gap junction proteins, are probably pannexins. They have a similar structure, but don't share any sequence homology.

[edit] Pathologies

[edit] List of Connexins

Connexin Gene
Location and Function
Cx23
Cx25
Cx26 GJB2
Cx30.2 Expressed in structures of the inner ear. Thought to have a role in ion transport for signal transduction in hair cells.[13]
Cx30 GJB6
Cx31.9 GJC1
Cx30.3 GJB4 Fonseca et al. confirmed Cx30.3 expression in thymocytes..[14]
Cx31 GJB3
Cx31.1 GJB5
Cx32 GJB1 Major component of the peripheral myelin. Its deletion causes significant developmental defects to the central nervous system.
Cx36 Pancreatic beta cell function, mediating the release of insulin.
Cx37 GJA4 Induced in vascular smooth muscle during coronary arteriogenesis. Cx37 mutations are not lethal. Forms gap junctions between oocytes and granulosa cells, and are requred for oocyte survival.
Cx40.1
Cx40 GJA5 Expressed selectively in atrial myocytes. Responsible for mediating the coordinated electrical activation of atria.[15]
Cx43 GJA1 Expressed at the surface of vasculature with atherosclerotic plaque, and up-regulated during atherosclerosis in mice. May have pathological effects. Also expressed between granulosa cells, which is required for proliferation.
Cx45 GJA7 Human pancreatic ductal epithelial cells. [16]
Cx46 GJA3
Cx47 GJA12
Cx50 GJA8
Cx59 GJA10
Cx62

[edit] References

  1. ^ Lodish, Harvey F., Arnold Berk, Paul Matsudaira, Chris A. Kaiser, Monty Krieger, Mathew P. Scott, S. Lawrence Zipursky, James Darnell (2004). Molecular Cell Biology, 5th Ed.. New York: W.H. Freeman and Company, 230-1.
  2. ^ Laird DW (March 2006). "Life cycle of connexins in health and disease.". The Biochemical Journal 394 (3): 527-43. PMID 16492141.
  3. ^ Laird DW (March 2006). "Life cycle of connexins in health and disease.". The Biochemical Journal 394 (3): 527-43. PMID 16492141.
  4. ^ Musil LS and Goodenough DA (1993). "Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER.". Cell 74: 1065–1077.
  5. ^ Evans, W. H., Ahmad, S., Diez, J., George, C. H., Kendall, J. M. and Martin, P. E. (1999). "Trafficking pathways leading to the formation of gap junctions". Novartis Found. Symp. 219: 44-54.
  6. ^ George, C. H., Kendall, J. M. and Evans, W. H. (1999). "Intracellular trafficking pathways in the assembly of connexins into gap junctions.". J. Biol. Chem. 274: 8678–8685.
  7. ^ George, C. H., Kendall, J. M., Campbell, A. K. and Evans, W. H. (1998). "Connexin–aequorin chimerae report cytoplasmic calcium environments along trafficking pathways leading to gap junction biogenesis in living COS-7 cells". J. Biol. Chem. 274: 29822–29829.
  8. ^ Martin, P. E., George, C. H., Castro, C., Kendall, J. M., Capel, J., Campbell, A. K., Revilla, A., Barrio, L. C. and Evans, W. H. (1998). "Assembly of chimeric connexin–aequorin proteins into functional gap junction channels. Reporting intracellular and plasma membrane calcium environments.". J. Biol. Chem. 273: 1719-1726.
  9. ^ Martin, P. E., Errington, R. J. and Evans, W. H. (2001). "Gap junction assembly: multiple connexin fluorophores identify complex trafficking pathways". Cell Commun. Adhes. 8: 243-248.
  10. ^ Thomas, T., Jordan, K., Simek, J., Shao, Q., Jedeszko, C., Walton, P. and Laird, D. W. (2005). "Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration". J. Cell Sci 118: 4451-4462.
  11. ^ Jongen, W. M., Fitzgerald, D. J., Asamoto, M., Piccoli, C., Slaga, T. J., Gros, D., Takeichi, M. and Yamasaki, H. (1991). "Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin.". J. Cell Biol. 114: 545–555.
  12. ^ Wei, C. J., Francis, R., Xu, X. and Lo, C. W. (2005). "Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells.". J. Biol. Chem. 280: 19925-36.
  13. ^ del Castillo I, et al. (Jan 24 2002). "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment". N Engl J Med 346 (4): 343-9. PMID 11807148.
  14. ^ Fonseca PC, Nihei OK, Urban-Maldonado M, Abreu S, de Carvalho AC, Spray DC, Savino W, Alves LA (June 2004). "Characterization of connexin 30.3 and 43 in thymocytes.". Immuno lett. 94 (1-2): 65-75. PMID 15234537.
  15. ^ Gollob MH, et al. (Jun 22 2006). "Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation". N Engl J Med 354 (25): 2677-88. PMID 16790700.
  16. ^ Tai M-H (2003). "Characterization of Gap Junctional Intercellular Communication in Immortalized Human Pancreatic Ductal Epithelial Cells With Stem Cell Characteristics". Pancreas (1): e18-e26.
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