Connexins, or gap junction

Gap junction

A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types. It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells....

 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 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

Cardiac muscle

Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth 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

In recent literature, connexins are most commonly named according to their molecular weights, e.g. Cx26 is the connexin protein of 26 kDa. However, this can lead to confusion 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

Myometrium

The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells , but also of supporting stromal and vascular tissue...

.

From the Nucleus to the Membrane

As they are being translated by ribosomes, connexins are inserted into the membrane of the endoplasmic reticulum

Endoplasmic reticulum

The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...

 (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

Endoplasmic reticulum

The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...

 and passing through the ERGIC

Vesicular-tubular cluster

A vesicular-tubular cluster , also referred to as the ER-Golgi intermediate compartment , is an organelle in eukaryotic cells. This compartment mediates trafficking between the endoplasmic reticulum and Golgi complex, facilitating the sorting of cargo...

, 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.

Function

Connexin gap junctions are found only in vertebrate

Vertebrate

Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...

s. A functionally analogous but genetically unrelated group of proteins, the pannexin

Pannexin

Pannexins are a family of vertebrate proteins identified by their homology to the invertebrate innexins...

s are expressed in both vertebrate and invertebrate

Invertebrate

An invertebrate is an animal without a backbone. The group includes 97% of all animal species – all animals except those in the chordate subphylum Vertebrata .Invertebrates form a paraphyletic group...

 species. The innexin

Innexin

An innexin is a member of a class of proteins which is used to create gap junctions in invertebrates. The innexin protein and its vertebrate homologue pannexin1 have 4 transmembrane spanning units and, like the vertebrate connexin gap junction protein, 6 innexin subunits together form a channel,...

 proteins, invertebrate gap junction proteins, are probably pannexins. They have a similar structure, but don't share any sequence homology.

Within the CNS

Central nervous system

The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

, 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

Retina

The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

, 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.

List of human connexins

Connexin	Gene	Location and Function
Cx43	GJA1 GJA1 -Interactions:Gap junction protein, alpha 1 has been shown to interact with MAPK7, Caveolin 1, Tight junction protein 1 CSNK1D, and PTPmu .-Further reading:...	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 mainly in ventricular myocardium. Associated with oculodentodigital dysplasia Oculodentodigital dysplasia Oculodentodigital syndrome is an extremely rare genetic condition that typically results in small eyes, underdeveloped teeth, and syndactyly and malformation of the fourth and fifth fingers. It has also been called oculo-dento-digital syndrome, oculodentodigital dysplasia , and oculodentoosseous... .
Cx46	GJA3 GJA3 Gap junction alpha-3 protein is a protein that in humans is encoded by the GJA3 gene.-Interactions:GJA3 has been shown to interact with Tight junction protein 1....
Cx37	GJA4 GJA4 Gap junction alpha-4 protein is a protein that in humans is encoded by the GJA4 gene....	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 GJA5 Gap junction alpha-5 protein is a protein that in humans is encoded by the GJA5 gene.- Function :This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of...	Expressed selectively in atrial myocytes. Responsible for mediating the coordinated electrical activation of atria.
Cx33	GJA6 (GJA6P)	Pseudogene Pseudogene Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...  in humans
Cx50	GJA8 GJA8 Gap junction alpha-8 protein is a protein that in humans is encoded by the GJA8 gene. It is also known as connexin 50.-Interactions:GJA8 has been shown to interact with Tight junction protein 1....	Gap Junctions between A-typ Horizontal cells in Mouse and Rabbit Retina
Cx59	GJA10 GJA10 Gap junction alpha-10 protein, also known as connexin-62 , is a protein that in humans is encoded by the GJA10 gene.Connexins, such as GJA10, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells...
Cx62	GJA10 GJA10 Gap junction alpha-10 protein, also known as connexin-62 , is a protein that in humans is encoded by the GJA10 gene.Connexins, such as GJA10, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells...	Human Cx62 complies Cx57 (Mouse). Location in axon-bearing B-typ Horizontal Cell in Rabbit Retina
Cx32	GJB1 GJB1 Gap junction beta-1 protein is a protein that in humans is encoded by the GJB1 gene.- Function :Connexins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells...	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.
Cx26	GJB2 GJB2 Gap junction beta-2 also known as connexin-26 is a protein that in humans is encoded by the GJB2 gene. Defects in this gene lead to the most common form of congenital deafness in developed countries, called DFNB1, also known as Connexin 26 deafness or GJB2-related deafness.- Function :Gap...	Mutated in Vohwinkel syndrome Vohwinkel syndrome Vohwinkel syndome is a diffuse autosomal dominant keratoderma with onset in early infancy characterized by a honeycombed keratoderma involving the palmoplantar surfaces...  as well as Keratitis-Icthyosis-Deafness (KID) Syndrome.
Cx31	GJB3 GJB3 Gap junction beta-3 protein is a protein that in humans is encoded by the GJB3 gene.- Function :This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of...	Can be associated with Erythrokeratodermia variabilis Erythrokeratodermia variabilis Erythrokeratodermia variabilis is a rare autosomal dominant disorder that usually presents at birth or during the... .
Cx30.3	GJB4 GJB4 Gap junction beta-4 protein is a protein that in humans is encoded by the GJB4 gene....	Fonseca et al. confirmed Cx30.3 expression in thymocyte Thymocyte Thymocytes are hematopoietic progenitor cells present in the thymus. Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes. The primary function of thymocytes is the generation of T lymphocytes . The thymus provides an inductive environment, which... s. Can be associated with Erythrokeratodermia variabilis Erythrokeratodermia variabilis Erythrokeratodermia variabilis is a rare autosomal dominant disorder that usually presents at birth or during the... .
Cx31.1	GJB5 GJB5 Gap junction beta-5 protein , also known as connexin-31.1 , is a protein that in humans is encoded by the GJB5 gene.- Function :...
Cx30	GJB6	Mutated in Clouston syndrome (hidrotic ectodermal dysplasia)
Cx25	GJB7 GJB7 Gap junction beta-7 protein , also known as connexin-25 , is a protein that in humans is encoded by the GJB7 gene.- Function :...
Cx45	GJC1/GJA7	Human pancreatic ductal epithelial cells. Atrio-ventricular node.
Cx47	GJC2 GJC2 Gap junction gamma-2 , also known as connexin-46.6 and connexin-47 and gap junction alpha-12 , is a protein that in humans is encoded by the GJC2 gene.- Function :This gene encodes a gap junction protein... /GJA12	Expressed in oligodentrocytes
Cx30.2	GJC3 GJC3 Gap junction gamma-3, also known as connexin-30.2 or connexin-31.3 or gap junction epsilon-1 , is a protein that in humans is encoded by the GJC3 gene.GJC3 is a connexin.- Function :...	Expressed in structures of the inner ear. Thought to have a role in ion transport for signal transduction in hair cells.
Cx36	GJD2 GJD2 Gap junction delta-2 protein also known as connexin-36 or gap junction alpha-9 protein and is a protein that in humans is encoded by the GJD2 gene.- Function :... /GJA9	Pancreatic beta cell function, mediating the release of insulin. Neurones throughout the Central Nervous System Central nervous system The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...  where they allow synchronisation of action potential Action potential In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...  firing between networks of neurones.
Cx31.9	GJD3 GJD3 Gap junction delta-2 , also known as connexin-36 or gap junction alpha-9 , is a protein that in humans is encoded by the GJD2 gene.- Function :... /GJC1
Cx39	GJD4 GJD4 Gap junction delta-4 protein , also known as connexin-40.1 , is a protein that in humans is encoded by the GJD4 gene.- Function :...
Cx40.1	GJD4 GJD4 Gap junction delta-4 protein , also known as connexin-40.1 , is a protein that in humans is encoded by the GJD4 gene.- Function :...
Cx23	GJE1
Cx29	GJE1