Gap junction
Gap junction
MeSH	Gap+Junctions
Code	TH H2.00.1.1.02024

A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types.^[1][2][3] It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells.^[4][5]

One gap junction channel is composed of two connexons (or hemichannels) which connect across the intercellular space.^[4][5][6] Gap junctions are analogous to the plasmodesmata that join plant cells.^[7]

Structure[link]

In vertebrates, gap junction hemichannels are primarily homo- or hetero-hexamers of connexin proteins. Invertebrate gap junctions comprise proteins from the hypothetical innexin family. However, the recently characterized pannexin family, which was originally thought to form intercellular channels (based on similar amino acid sequence similarity to innexins), in fact functions as single-membrane channels that communicate with the extracellular environment, and have been shown to pass calcium and ATP.

At gap junctions, the intercellular space is 4 nm^[6] and unit connexons in the membrane of each cell are lined up with one another.^[8]

Gap junction channels formed from two identical hemichannels are called homotypic, while those with differing hemichannels are heterotypic. In turn, hemichannels of uniform connexin composition are called homomeric, while those with differing connexins are heteromeric. Channel composition is thought to influence the function of gap junction channels.

Generally, the genes coding for gap junction channels are classified in one of three groups, based on sequence similarity: A, B and C (for example, GJA1, GJC1). However, genes do not code directly for the expression of gap junction channels; genes can only produce the proteins which make up gap junction channels (connexins). An alternative naming system based on this protein's molecular weight is also popular (for example: connexin43, connexin30.3).

Levels of organization[link]

1. DNA to RNA to Connexin protein.
2. One connexin protein has four transmembrane domains
3. 6 Connexins create one Connexon (hemichannel). When different connexins join together to form one connexon, it is called a heteromeric connexon
4. Two hemichannels, joined together across a cell membrane comprise a Gap Junction channel.
   When two identical connexons come together to form a Gap junction channel, it is called a homotypic GJ channel. When one homomeric connexon and one heteromeric connexon come together, it is called a heterotypic gap junction channel. When two heteromeric connexons join, it is also called a heteromeric Gap Junction channel.
5. Several gap junction channels (hundreds) assemble into a macromolecular complex called a gap junction.

Properties[link]

1. Allows for direct electrical communication between cells, although different connexin subunits can impart different single channel conductances, from about 30 pS to 500 pS.
2. Allows for chemical communication between cells, through the transmission of small second messengers, such as inositol triphosphate (IP₃) and calcium (Ca²⁺),^[7] although different connexin subunits can impart different selectivity for particular small molecules.
3. Generally allows molecules smaller than 1,111 Daltons to pass through, although different connexin subunits can impart different pore sizes and different charge selectivity. Large biomolecules, for example, nucleic acid and protein, are precluded from cytoplasmic transfer between cells.
4. Ensures that molecules and current passing through the gap junction do not leak into the intercellular space.

To date, five different functions have been ascribed to gap junction protein: a) electrical and metabolic coupling between cells b) Electrical and metabolic exchange through hemichannels c) Tumor suppressor genes (Cx43, Cx32 and Cx36) d) Adhesive function independent of conductive gap junction channel (neural migration in neocortex) e) Role of carboxyl-terminal in signaling cytoplasmic pathways (Cx43)

Areas of electrical coupling[link]

Heart[link]

Gap junctions are particularly important in cardiac muscle: the signal to contract is passed efficiently through gap junctions, allowing the heart muscle cells to contract in tandem. Gap junctions are expressed in virtually all tissues of the body, with the exception of adult fully developed skeletal muscle and mobile cell types such as sperm or erythrocytes. Several human genetic disorders are associated with mutations in gap junction genes. Many of those affect the skin because this tissue is heavily dependent upon gap junction communication for the regulation of differentiation and proliferation.

Neurons[link]

A gap junction located in neurons is often referred to as an electrical synapse. The electrical synapse was discovered using electrical measurements before the gap junction structure was described. Few locations have been discovered where there is significant coupling between neurons in the brain. Structures in the brain that have been shown to contain electrically coupled neurons include the vestibular nucleus, the nucleus of trigeminal nerve, the inferior olivary nucleus, and the Ventral Tegmental Area. There has been some observation of weak neuron to glial cell coupling in the locus coeruleus, and in the cerebellum between Purkinje neurons and Bergmann glial cells. It now seems that astrocytes are strongly coupled by gap junctions.^{[citation needed]} Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in Pelizaeus-Merzbacher disease and multiple sclerosis.

Connexin proteins expressed in neurons include:

1. mCX26
2. mCX43
3. mCX36
4. mCX56.6
5. mCX57
6. mCX45

Retina[link]

Neurons within the retina show extensive coupling, both within populations of one cell type, and between different cell types.

Discovery[link]

Gap junctions were so named because of the "gap" shown to be present at these special junctions between two cells.^[9] A similar regular gap was not demonstrated in other intercellular junctions described at the time. Well before this demonstration of the "gap" in gap junctions they were seen at the junction of neighboring nerve cells ^[10][11][12] and proven to be electrically rectifying and so referred to as an electrical synapse.^[13][14] Because of the widespread occurrence of gap junctions in cell types other than nerve cells the term gap junction became more generally used than the term electrical synapse. Another dimension in the relationship between nerve cells and gap junctions was revealed by studying chemical synapse formation and gap junction presence. By tracing nerve development in leeches with gap junction expression suppressed it was shown that the electrical synapse may be a necessary precursor to the development of a chemical synapse^[15].

With the purification^[16][17] of the intercellular gap junction plaques enriched in the channel forming protein (connexin) more systematic study and identification of the gap junction protein^[18] became possible. Refined ultrastructural studies^[19] showed the protein occurred in a complementary fashion in both cells participating in a gap junction plaque. The gap junction plaque is a relatively large area of membrane seen filled with gap junction proteins in both tissues and more gently treated gap junction preparations. With the apparent ability for one protein alone to enable intercellular communication seen in gap junctions^[20] the term gap junction tended to became synonymous with a group of assembled connexins though this was not shown in vivo. Biochemical analysis of gap junction rich isolates from various tissues demonstrated a family of connexins.^[21][22][23]

Ultrastructure and biochemistry of gap junctions already referenced had indicated the connexins preferentially group in gap junction plaques or domains and connexins were the only constituent. Combining ultrastructure with immunocytochemistry showed gap junction plaques in vivo initially supported the idea that gap junctions plaques could be defined by the presence of connexins.^[24][25] However later studies showed gap junction plaques are home to non-connexin proteins as well making the modern usage of the term gap junction and gap junction plaque non-interchangeable.^[26][27]

See also[link]

• Electrical synapse
• Ion channel
• Junctional complex
• Intercalated disc
• Cardiac muscle
• Tight junction
• Desmosomes

References[link]

Further reading[link]

• Harris, Andrew; Locke, Darren, eds. (2009). Connexins. New York: Springer. ISBN 978-1-934115-46-6. http://www.springer.com/978-1-934115-46-6. 

External links[link]

• Gap+Junctions at the US National Library of Medicine Medical Subject Headings (MeSH)