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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]

gap junction

One gap junction 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]

A notable use of gap junctions is in the electrical synapse found in some neurons.



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 junctions 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 junctions 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 junctions; genes can only produce the proteins which make up gap junctions (connexins). An alternative naming system based on this protein's molecular weight is also popular (for example: connexin43, connexin30.3).

Levels of organization

  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.
    When two identical connexons come together to form a Gap junction, it is called a homotypic GJ. When one homomeric connexon and one heteromeric connexon come together, it is called a heterotypic gap junction. When two heteromeric connexons join, it is also called a heteromeric Gap Junction.
  5. Several gap junctions (hundreds) assemble into a macromolecular complex called a plaque.


  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 1,000 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



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 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.


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] Experimental data show strong gap junction expression in astrocytes. 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


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


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. With the purification[15][16] of the intercellular gap junction plaques enriched in the channel forming protein (connexin) more systematic study and identification of the gap junction protein[17] became possible. Refined ultrastructural studies[18] 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[19] 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.[20][21][22] 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.[23][24] 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.[25][26]

See also


  1. ^ White, Thomas W.; Paul, David L. (1999). "Genetic diseases and gene knockouts reveal diverse connexin functions". Annual review of physiology 61: 283–310. doi:10.1146/annurev.physiol.61.1.283. PMID 10099690. 
  2. ^ Kelsell, David P.; Dunlop, John; Hodgins, Malcolm B. (2001). "Human diseases: clues to cracking the connexin code?". Trends in cell biology 11 (1): 2–6. doi:10.1016/S0962-8924(00)01866-3. PMID 11146276. 
  3. ^ Willecke, Klaus; Eiberger, Jürgen; Degen, Joachim; Eckardt, Dominik; Romualdi, Alessandro; Güldenagel, Martin; Deutsch, Urban; Söhl, Goran (2002). "Structural and functional diversity of connexin genes in the mouse and human genome". Biological chemistry 383 (5): 725–37. doi:10.1515/BC.2002.076. PMID 12108537. 
  4. ^ a b Lampe, Paul D.; Lau, Alan F. (2004). "The effects of connexin phosphorylation on gap junctional communication". The international journal of biochemistry & cell biology 36 (7): 1171–86. doi:10.1016/S1357-2725(03)00264-4. PMID 15109565. 
  5. ^ a b Lampe, Paul D.; Lau, Alan F. (2000). "Regulation of gap junctions by phosphorylation of connexins". Archives of biochemistry and biophysics 384 (2): 205–15. doi:10.1006/abbi.2000.2131. PMID 11368307. 
  6. ^ a b Maeda, Shoji; Nakagawa, So; Suga, Michihiro; Yamashita, Eiki; Oshima, Atsunori; Fujiyoshi, Yoshinori; Tsukihara, Tomitake (2009). "Structure of the connexin 26 gap junction channel at 3.5 A resolution". Nature 458 (7238): 597–602. doi:10.1038/nature07869. PMID 19340074. 
  7. ^ a b Alberts, Bruce (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1. 
  8. ^ Perkins, Guy A.; Goodenough, Daniel A.; Sosinsky, Gina E. (1998). "Formation of the gap junction intercellular channel requires a 30 degree rotation for interdigitating two apposing connexons". Journal of molecular biology 277 (2): 171–7. doi:10.1006/jmbi.1997.1580. PMID 9514740. 
  9. ^ Revel, J. P.; Karnovsky, M. J. (1967). "Hexagonal array of subunits in intercellular junctions of the mouse heart and liver". The Journal of cell biology 33 (3): C7–C12. doi:10.1083/jcb.33.3.C7. PMID 6036535. 
  10. ^ Robertson, J. D. (1953). "Ultrastructure of two invertebrate synapses". Proceedings of the Society for Experimental Biology and Medicine 82 (2): 219–23. PMID 13037850. 
  11. ^ Robertson, J. D. (1963). Locke, Michael. ed. Cellular membranes in development. New York: Academic Press. OCLC 261587041. 
  12. ^ Robertson (1981). "Membrane Structure". The Journal of Cell Biology 91 (3): 189s-204s. doi:10.1083/jcb.91.3.189s. PMID 7033238. PMC 2112820. 
  13. ^ Furshpan, E. J. (1957). "Mechanism of Nerve-Impulse Transmission at a Crayfish Synapse". Nature 180 (4581): 342. doi:10.1038/180342a0. PMID 13464833. 
  14. ^ Furshpan (1959). "Transmission at the giant motor synapses of the crayfish". The Journal of physiology 145 (2): 289–325. PMID 13642302. PMC 1356828. 
  15. ^ Goodenough, D. A. (1972). "The isolation of mouse hepatocyte gap junctions. Preliminary chemical characterization and x-ray diffraction". The Journal of Cell Biology 54 (3): 646. doi:10.1083/jcb.54.3.646. PMID 4339819. 
  16. ^ Goodenough, D. A. (1974). "Bulk isolation of mouse hepatocyte gap junctions. Characterization of the principal protein, connexin". The Journal of Cell Biology 61 (2): 557. doi:10.1083/jcb.61.2.557. PMID 4363961. 
  17. ^ Kumar, N. M. (1986). "Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein". The Journal of Cell Biology 103 (3): 767. doi:10.1083/jcb.103.3.767. PMID 2875078. 
  18. ^ Chalcroft, J. P. (1970). "An interpretation of liver cell membrane and junction structure based on observation of freeze-fracture replicas of both sides of the fracture". The Journal of Cell Biology 47 (1): 49. doi:10.1083/jcb.47.1.49. PMID 4935338. 
  19. ^ Young (1987). "Functional assembly of gap junction conductance in lipid bilayers: demonstration that the major 27 kd protein forms the junctional channel". Cell 48 (5): 733–43. doi:10.1016/0092-8674(87)90071-7. PMID 3815522. 
  20. ^ Nicholson (1985). "The Mr 28,000 gap junction proteins from rat heart and liver are different but related". The Journal of biological chemistry 260 (11): 6514–7. PMID 2987225. 
  21. ^ Beyer, E. C. (1987). "Connexin43: a protein from rat heart homologous to a gap junction protein from liver". The Journal of Cell Biology 105 (6 Pt 1): 2621. doi:10.1083/jcb.105.6.2621. PMID 2826492. 
  22. ^ Kistler (1985). "Identification of a 70,000-D protein in lens membrane junctional domains". The Journal of cell biology 101 (1): 28–35. doi:10.1083/jcb.101.1.28. PMID 3891760. 
  23. ^ Gruijters (1987). "Immunolocalization of MP70 in lens fiber 16-17-nm intercellular junctions". The Journal of cell biology 104 (3): 565–72. doi:10.1083/jcb.104.3.565. PMID 3818793. 
  24. ^ Gruijters, WT (1987). "Formation, distribution and dissociation of intercellular junctions in the lens". Journal of Cell Science 88 (3): 351. PMID 3448099. 
  25. ^ Gruijters, WT (1989). "A non-connexon protein (MIP) is involved in eye lens gap-junction formation". Journal of Cell Science 93 (3): 509. PMID 2691517. 
  26. ^ Gruijters, W (2003). "Are gap junction membrane plaques implicated in intercellular vesicle transfer?". Cell Biology International 27 (9): 711. doi:10.1016/S1065-6995(03)00140-9. PMID 12972275. 

Further reading

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