View source for Connexin

[[Image:biggapjunct2.png|thumb|200px|An open gap junction, comprised of 6 connexins.]]
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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]]).<ref>{{cite book| last = Lodish | first = Harvey F. | coauthors = Arnold Berk, Paul Matsudaira, Chris A. Kaiser, Monty Krieger, Mathew P. Scott, S. Lawrence Zipursky, James Darnell | title = Molecular Cell Biology | edition = 5th Ed. | publisher = W.H. Freeman and Company | date = 2004 | location = New York | pages = 230-1 | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mcb.TOC&depth=10 | isbn = 	
0-7167-4366-3}}</ref> Each gap junction comprises 2 hemichannels, or "connexons", which are themselves each constructed out of 6 '''connexin''' molecules. Gap junctions are essential for many physiological processes, such as the coordinated depolarization of [[cardiac muscle]], and proper embryonic development. For this reason, mutations in connexin-encoding genes can lead to functional and developmental abnormalities.

==Structure==
[[Image:Connexon and connexin structure.svg|thumb|left|300px]]
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, and two hemichannels then combine to form a gap junction. The connexin gene family is diverse, with 21 identified members in the sequenced human genome, and 20 in the mouse (19 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==
In recent literature, connexins are most commonly named according to their molecular weights, e.g. Cx26 is the connexin protein of 26 kDa. This can lead to confusion however when connexin genes from different species are compared, e.g. human Cx36 is homologous to [[zebra danio|zebrafish]] Cx35.  A competing nomenclature is the Gja/Gjb system, where connexins are sorted by their α and β forms, then assigned an identifying number, e.g. Gja1 corresponds to Cx43. The nomenclature of the connexin genes and proteins is currently under review by the [http://www.gene.ucl.ac.uk/nomenclature/genefamily/gj.html HUGO Gene Nomenclature Committee].

==Biosynthesis and Internalization==

A remarkable aspect of connexins is that they have a relatively short half life of only a few hours.<ref name="Laird2006">{{cite journal | author = Laird DW | title = Life cycle of connexins in health and disease. | journal = The Biochemical Journal | volume = 394 | issue = 3 | pages = 527-43 | year = 2006 | month = March | id = PMID 16492141 }}</ref> 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.<ref name="Laird2006"> </ref> The arrangements of these hemichannels can be homotypic, heterotypic, and combined heterotypic/heteromeric. 

After exiting the [[Endoplasmic reticulum|ER]] and passing through the ERGIC, the folded connexins will usually enter the ''cis''-Golgi network.<ref>{{ cite journal | last = Musil | first = LS | coauthors = Goodenough DA | year = 1993 | title = Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER | journal = Cell | volume = 74 | pages = 1065–1077 | pmid = 7691412 }}</ref> However, some connexins, such as Cx26 may be transported independent of the Golgi.<ref>{{ cite journal | last = Evans | first = W. H.| coauthors = Ahmad, S., Diez, J., George, C. H., Kendall, J. M. and Martin, P. E. | year = 1999  | title = Trafficking pathways leading to the formation of gap junctions | journal = Novartis Found. Symp. | volume = 219 | pages = 44-54 }}</ref><ref>{{ cite journal | author = George, C. H., Kendall, J. M. and Evans, W. H. | year =1999  | title = Intracellular trafficking pathways in the assembly of connexins into gap junctions. | journal = J. Biol. Chem.  | volume = 274 | pages = 8678–8685}}</ref><ref>{{ cite journal | author = George, C. H., Kendall, J. M., Campbell, A. K. and Evans, W. H. | year = 1998  | title = Connexin–aequorin chimerae report cytoplasmic calcium environments along trafficking pathways leading to gap junction biogenesis in living COS-7 cells | journal = J. Biol. Chem. | volume = 274 | pages = 29822–29829 }}</ref><ref>{{ cite journal | author = 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.  | year = 1998 | title = Assembly of chimeric connexin–aequorin proteins into functional gap junction channels. Reporting intracellular and plasma membrane calcium environments. | journal =  J. Biol. Chem. | volume = 273 | pages = 1719-1726}}</ref><ref>{{ cite journal | author = Martin, P. E., Errington, R. J. and Evans, W. H. | year = 2001 | title = Gap junction assembly: multiple connexin fluorophores identify complex trafficking pathways | journal = Cell Commun. Adhes. | volume = 8 | pages = 243-248 }}</ref>

===Gap Junction Assembly===
After being inserted into the plasma membrane of the cell, the hemichannels freely diffuse within the lipid bilayer.<ref>{{ cite journal | author = Thomas, T., Jordan, K., Simek, J., Shao, Q., Jedeszko, C., Walton, P. and Laird, D. W. | year = 2005 | title = Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration  | journal = J. Cell Sci | volume = 118 | pages = 4451-4462}}</ref> Through the aid of specific proteins, mainly [[cadherins]], the hemichannels are able to dock with hemichannels of adjacent cells forming gap junctions.<ref>{{ cite journal | author = Jongen, W. M., Fitzgerald, D. J., Asamoto, M., Piccoli, C., Slaga, T. J., Gros, D., Takeichi, M. and Yamasaki, H. | year = 1991 | title = Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin. | journal = J. Cell Biol.  | volume = 114 | pages = 545–555}}</ref> Recent studies have shown the existence of communication between adherens junctions and gap junctions,<ref>{{ cite journal | author = Wei, C. J., Francis, R., Xu, X. and Lo, C. W. | year = 2005 | title = Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells. | journal = J. Biol. Chem. | volume = 280 | pages = 19925-36 }}</ref> suggesting a higher level of coordination than previously thought.

==Function==

Connexin gap junctions are found only in [[vertebrate]]s. A functionally analogous but genetically unrelated group of proteins, the [[pannexin]]s 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.

==Pathologies==
==List of Connexins==

{| cellpadding=3 cellspacing=0 border=1 style="border-collapse:collapse"
|bgcolor="#99CCCC"| '''Connexin'''
|bgcolor="#99CCCC"| '''Gene'''
|bgcolor="#99CCCC"| <center>'''Location and Function'''</center>
|-
|Cx23 
|
|
|-
|Cx25 
|
|
|- 
|Cx26 
|[[GJB2]]
| Mutated in Vohwinkel's mutilating palmoplantar keratoderma (PPCK) associated with deafness as well as Keratitis-Icthyosis-Deafness (KID) Synrdome.
|- 
|Cx30.2  
|
|Expressed in structures of the inner ear. Thought to have a role in ion transport for signal transduction in hair cells.<ref>{{cite journal | author = del Castillo I, et al.| title = A  deletion involving the connexin 30 gene in nonsyndromic hearing impairment| journal = N Engl J Med | volume = 346| issue = 4| pages = 343-9| year = 2002| month = January 24| id = PMID 11807148}}</ref>
|-
|Cx30 
|{{Gene|GJB6}}
| Mutated in Clouston syndrome (hidrotic ectodermal dysplasia)
|-
|Cx31.9 
|{{Gene|GJC1}}
|
|-
|Cx30.3 
|{{Gene|GJB4}}
|Fonseca ''et al.'' confirmed Cx30.3 expression in [[thymocyte]]s.<ref>{{cite journal | author = Fonseca PC, Nihei OK, Urban-Maldonado M, Abreu S, de Carvalho AC, Spray DC, Savino W, Alves LA| title = Characterization of connexin 30.3 and 43 in thymocytes.| journal = Immuno lett. | volume = 94| issue = 1-2| pages = 65-75| year = 2004| month = June| id = PMID 15234537}}</ref>
|-
|Cx31 
|{{Gene|GJB3}}
|
|-
|Cx31.1 
|{{Gene|GJB5}}
|
|-
|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.<ref name="Aronica">{{cite journal |author=Aronica E, Gorter J, Jansen G et al |title=Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex |journal=Acta Neuropathol. |volume=101 |issue=5 |pages=449-59 |year=2001 |pmid=11484816}}</ref>
|-
|Cx36 
|
|Pancreatic beta cell function, mediating the release of insulin.  [[Neurones]] throughout the [[Central Nervous System]] where they allow sychonisation of [[action potential]] firing between networks of neurones.<ref>{{cite journal | author = Connors BW, Long MA | title = Electrical synapses in the mammalian brain. | journal = Annu Rev Neurosci | volume = 27 | pages = 393-418 | year = 2004 | pmid = 15217338}}</ref>
|-
|Cx37 
|{{Gene|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.
|- 
|Cx40.1 
|
|
|- 
|Cx40 
|[[GJA5]]
|Expressed selectively in atrial myocytes. Responsible for mediating the coordinated electrical activation of atria.<ref>{{cite journal | author = Gollob MH, et al.| title = Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation| journal = N Engl J Med | volume = 354| issue = 25| pages = 2677-88| year = 2006| month = June 22| id = PMID 16790700}}</ref>
|- 
|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. It is also the main cardiac connexin, found in all four chambers.<ref name="Aronica"> </ref>
|- 
|Cx45 
|{{Gene|GJA7}}
|Human pancreatic ductal epithelial cells.<ref>{{cite journal | author = Tai M-H | year = 2003 | title = Characterization of Gap Junctional Intercellular Communication in Immortalized Human Pancreatic Ductal Epithelial Cells With Stem Cell Characteristics | journal = Pancreas | vol = 26| issue = 1 | pages = e18-e26 }}</ref> Atrio-ventricular node.
|-
|Cx46 
|{{Gene|GJA3}}
|
|-
|Cx47 
|{{Gene|GJA12}}
|Expressed in oligodentrocytes

|-
|Cx50 
|{{Gene|GJA8}}
|
|-
|Cx59 
|{{Gene|GJA10}}
|
|- 
|Cx62 
|
|
</center>
|}

== References ==
{{Reflist|2}}

==External links==
* {{MeshName|Connexins}}

[[Category:Integral membrane proteins]]

[[de:Connexin]]
[[es:Conexina]]
[[fi:Konneksiini]]

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