Connexin

Connexin

An open gap junction, composed of six identical connexin proteins. Each of these six units is a single polypeptide which passes the membrane four times (referred to as four-pass transmembrane proteins).
Identifiers
Symbol Connexin
Pfam PF00029
InterPro IPR013092
PROSITE PDOC00341
TCDB 1.A.24
OPM superfamily 215
OPM protein 2zw3

Connexins, or gap junction proteins, are a family of structurally related transmembrane proteins that assemble to form vertebrate gap junctions (an entirely different family of proteins, the innexins, form gap junctions in invertebrates).[1] Each gap junction is composed of two hemichannels, or connexons, which are themselves each constructed out of six connexin molecules. Gap junctions are essential for many physiological processes, such as the coordinated depolarization of cardiac muscle, proper embryonic development, and the conducted response in microvasculature. For this reason, mutations in connexin-encoding genes can lead to functional and developmental abnormalities.

Structure

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 in groups of six to form hemichannels, or connexons, and two hemichannels then combine to form a gap junction. The connexin gene family is diverse, with twenty-one identified members in the sequenced human genome, and twenty in the mouse (nineteen of which are orthologous pairs). They usually weigh between 26 and 60 kDa, and have an average length of 380 amino acids. The various connexins have been observed to combine into both homomeric and heteromeric gap junctions, each of which may exhibit different functional properties including pore conductance, size selectivity, charge selectivity, voltage gating, and chemical gating.

Nomenclature

The term Connexin is abbreviated as Cx or CX. In recent literature, connexins are commonly named according to their molecular weights, e.g. Cx26 is the connexin protein of 26 kDa. However, this can lead to confusion when connexins from different species are compared, e.g. human Cx36 is homologous to zebrafish Cx35. A competing nomenclature is the GJ (gap junction) system, where connexins are sorted by their α (GJA) and β (GJB) forms, with additional connexins grouped into the C, D and E groupings, followed by an identifying number, e.g. GJA1/Gja1 corresponds to CX43/Cx43. Following a vote at the Gap Junction Conference (2007) in Elsinore the community agreed to use the GJ nomenclature system for the genes that encode connexins, but wished to retain the connexin nomenclature for the encoded proteins using the weight of the human protein for the numbering of orthologous proteins.

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.

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.[2] The arrangements of these hemichannels can be homotypic, heterotypic, and combined heterotypic/heteromeric.

After exiting the ER and passing through the ERGIC, the folded connexins will usually enter the cis-Golgi network.[3] However, some connexins, such as Cx26 may be transported independent of the Golgi.[4][5][6][7][8]

Gap Junction Assembly

After being inserted into the plasma membrane of the cell, the hemichannels freely diffuse within the lipid bilayer.[9] Through the aid of specific proteins, mainly cadherins, the hemichannels are able to dock with hemichannels of adjacent cells forming gap junctions.[10] Recent studies have shown the existence of communication between adherens junctions and gap junctions,[11] suggesting a higher level of coordination than previously thought.

Life cycle and protein associations of connexins. Connexins are synthesized on ER-bound ribosomes and inserted into the ER cotranslationally. This is followed by oligomerization between the ER and trans-Golgi network (depending on the connexin type) into connexons, which are then delivered to the membrane via the actin or microtubule networks. Connexons may also be delivered to the plasma membrane by direct transfer from the rough ER. Upon insertion into the membrane, connexons may remain as hemichannels or they dock with compatible connexons on adjacent cells to form gap junctions. Newly delivered connexons are added to the periphery of pre-formed gap junctions, while the central "older" gap junction fragment are degraded by internalization of a double-membrane structure called an annular junction into one of the two cells, where subsequent lysosomal or proteasomal degradation occurs, or in some cases the connexons are recycled to the membrane (indicated by dashed arrow). During their life cycle, connexins associate with different proteins, including (1) cytoskeletal components as microtubules, actin, and actin-binding proteins α-spectrin and drebrin, (2) junctional molecules including adherens junction components such as cadherins, α-catenin, and β-catenin, as well as tight junction components such as ZO-1 and ZO-2, (3) enzymes such as kinases and phosphatases which regulate the assembly, function, and degradation, and (4) other proteins such as caveolin. Dbouk et al., 2009.[12]

Function

Connexin gap junctions are found only in vertebrates, while a functionally analogous (but genetically unrelated) group of proteins, the innexins, are responsible for gap junctions in invertebrate species. Innexin orthologs have also been identified in Chordates, but they are no longer capable of forming gap junctions. Instead, the channels formed by these proteins (called pannexins) act as very large transmembrane pores that connect the intra- and extracellular compartments.

Within the CNS, gap junctions provide electrical coupling between progenitor cells, neurons, and glial cells. By using specific connexin KO mice, studies revealed that cell coupling is essential for visual signaling. In the retina, ambient light levels influence cell coupling provided by gap junction channels, adapting the visual function for various lighting conditions. Cell coupling is governed by several mechanisms, including connexin expression.[13]

List of human connexins

Connexin Gene Location and Function
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. Normally expressed in astrocytes, also detected in most of the human astrocytomas and in the astroglial component of glioneuronal tumors.[14] It is also the main cardiac connexin, found mainly in ventricular myocardium.[15] Associated with oculodentodigital dysplasia.
Cx46 GJA3
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 required for oocyte survival.
Cx40 GJA5 Expressed selectively in atrial myocytes. Responsible for mediating the coordinated electrical activation of atria.[16]
Cx33 GJA6
(GJA6P)		 Pseudogene in humans
Cx50 GJA8 Gap Junctions between A-typ Horizontal cells in Mouse and Rabbit Retina[17]
Cx59 GJA10
Cx62 GJA10 Human Cx62 complies Cx57 (Mouse). Location in axon-bearing B-typ Horizontal Cell in Rabbit Retina[18]
Cx32 GJB1 Major component of the peripheral myelin. Mutations in the human gene cause X-linked Charcot-Marie-Tooth disease, a hereditary neuropathy. In human normal brain CX32 expressed in neurons and oligodendrocytes.[14]
Cx26 GJB2 Mutated in Vohwinkel syndrome as well as Keratitis-Icthyosis-Deafness (KID) Syndrome.
Cx31 GJB3 Can be associated with Erythrokeratodermia variabilis.
Cx30.3 GJB4 Fonseca et al. confirmed Cx30.3 expression in thymocytes.[19] Can be associated with Erythrokeratodermia variabilis.
Cx31.1 GJB5
Cx30 GJB6 Mutated in Clouston syndrome (hidrotic ectodermal dysplasia)
Cx25 GJB7
Cx45 GJC1/GJA7 Human pancreatic ductal epithelial cells.[20] Atrio-ventricular node.
Cx47 GJC2/GJA12 Expressed in oligodentrocyte gap junctions[21]
Cx30.2 GJC3 Expressed in structures of the inner ear. Thought to have a role in ion transport for signal transduction in hair cells.[22]
Cx36 GJD2/GJA9 Pancreatic beta cell function, mediating the release of insulin. Neurons throughout the Central Nervous System where they synchronize neural activity.[23]
Cx31.9 GJD3/GJC1
Cx39 GJD4
Cx40.1 GJD4
Cx23 GJE1
Cx29 GJE1 Not known to form gap junctions; present in innermost layer of myelin in Schwann cells[24]

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. pp. 230–1. ISBN 0-7167-4366-3.
  2. 1 2 Laird DW (March 2006). "Life cycle of connexins in health and disease". The Biochemical Journal 394 (3): 527–43. doi:10.1042/BJ20051922. PMC 1383703. PMID 16492141.
  3. ↑ Musil, LS; Goodenough DA (1993). "Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER". Cell 74 (6): 1065–77. doi:10.1016/0092-8674(93)90728-9. PMID 7691412.
  4. ↑ Evans, W. H.; Ahmad, S.; Diez, J.; George, C. H.; Kendall, J. M.; Martin, P. E. (1999). "Trafficking pathways leading to the formation of gap junctions". Novartis Found. Symp. Novartis Foundation Symposia 219: 44–54. doi:10.1002/9780470515587.ch4. ISBN 978-0-470-51558-7. PMID 10207897.
  5. ↑ 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 (13): 8678–85. doi:10.1074/jbc.274.13.8678. PMID 10085106.
  6. ↑ 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 (45): 29822–9. doi:10.1074/jbc.273.45.29822. PMID 9792698.
  7. ↑ 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 (3): 1719–26. doi:10.1074/jbc.273.3.1719. PMID 9430718.
  8. ↑ 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 (4–6): 243–8. doi:10.3109/15419060109080731. PMID 12064596.
  9. ↑ 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 (Pt 19): 4451–62. doi:10.1242/jcs.02569. PMID 16159960.
  10. ↑ 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 (3): 545–555. doi:10.1083/jcb.114.3.545. PMC 2289094. PMID 1650371.
  11. ↑ 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 (20): 19925–36. doi:10.1074/jbc.M412921200. PMID 15741167.
  12. ↑ Dbouk HA, Mroue RM, El-Sabban ME, Talhouk RS (2009). "Connexins: a myriad of functions extending beyond assembly of gap junction channels". Cell Commun. Signal 7: 4. doi:10.1186/1478-811X-7-4. PMC 2660342. PMID 19284610.
  13. ↑ Kihara AH, de Castro LM, Moriscot AS, Hamassaki DE. (May 2006). "Prolonged dark adaptation changes connexin expression in the mouse retina". J Neurosci Res 83 (7): 1331–41. doi:10.1002/jnr.20815. PMID 16496335.
  14. 1 2 Aronica E; Gorter J; Jansen G; et al. (2001). "Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex". Acta Neuropathol. 101 (5): 449–59. doi:10.1007/s004010000305. PMID 11484816.
  15. ↑ Verheule S, van Kempen MJ, te Welscher PH, Kwak BR, Jongsma HJ (May 1997). "Characterization of gap junction channels in adult rabbit atrial and ventricular myocardium". Circ. Res. 80 (5): 673–81. doi:10.1161/01.res.80.5.673. PMID 9130448.
  16. ↑ Gollob MH; et al. (June 22, 2006). "Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation". N Engl J Med 354 (25): 2677–88. doi:10.1056/NEJMoa052800. PMID 16790700.
  17. ↑ Massey, Stephen (16 January 2009). Connexins: A Guide (1st ed.). Springer-Verlag Gmbh. pp. 3–?. ISBN 1-934115-46-0.
  18. ↑ Beyer, Eric C.; Berthound, Viviana M. (16 January 2009). Connexins: A Guide (1st ed.). Springer-Verlag Gmbh. pp. 387–417. ISBN 1-934115-46-0.
  19. ↑ 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. doi:10.1016/j.imlet.2004.03.019. PMID 15234537.
  20. ↑ Tai M-H; Olson, LK; Madhukar, BV; Linning, KD; Van Camp, L; Tsao, MS; Trosko, JE (2003). "Characterization of Gap Junctional Intercellular Communication in Immortalized Human Pancreatic Ductal Epithelial Cells With Stem Cell Characteristics". Pancreas 26 (1): e18–e26. doi:10.1097/00006676-200301000-00025. PMID 12499933.
  21. ↑ Kamasawa N, Sik A, Morita M; et al. (2005). "Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt-Lanterman incisures: implications for ionic homeostasis and potassium siphoning". Neuroscience 136 (1): 65–86. doi:10.1016/j.neuroscience.2005.08.027. PMC 1550704. PMID 16203097.
  22. ↑ del Castillo I; et al. (January 24, 2002). "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment". N Engl J Med 346 (4): 343–9. doi:10.1056/NEJMoa012052. PMID 11807148.
  23. ↑ Connors BW, Long MA (2004). "Electrical synapses in the mammalian brain". Annu Rev Neurosci 27: 393–418. doi:10.1146/annurev.neuro.26.041002.131128. PMID 15217338.
  24. ↑ Li X, Lynn BD, Olson C; et al. (September 2002). "Connexin29 expression, immunocytochemistry and freeze-fracture replica immunogold labelling (FRIL) in sciatic nerve". Eur. J. Neurosci. 16 (5): 795–806. doi:10.1046/j.1460-9568.2002.02149.x. PMC 1803218. PMID 12372015.

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