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). 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.
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.
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 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 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. 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. 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. However, some connexins, such as Cx26 may be transported independent of the Golgi.
Gap Junction Assembly
After being inserted into the plasma membrane of the cell, the hemichannels freely diffuse within the lipid bilayer. Through the aid of specific proteins, mainly cadherins, the hemichannels are able to dock with hemichannels of adjacent cells forming gap junctions. Recent studies have shown the existence of communication between adherens junctions and gap junctions, suggesting a higher level of coordination than previously thought.
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.
List of Connexins
|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.|
|Cx30||GJB6||Mutated in Clouston syndrome (hidrotic ectodermal dysplasia)|
|Cx30.3||GJB4||Fonseca et al. confirmed Cx30.3 expression in thymocytes.|
|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.|
|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.|
|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.|
|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.|
|Cx45||GJA7||Human pancreatic ductal epithelial cells. Atrio-ventricular node.|
|Cx47||GJA12||Expressed in oligodentrocytes|
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