2011 Group 2 Project

From CellBiology

Gap Junctions


Direct interactions of cells with their neighbouring cells or extracellular matrix at particular site of contact are called cell junctions. [1]

Cell junctions.jpg

Cell junctions can be categorized functionally into three groups:

1. Occluding junctions

2. Anchoring junctions

3. Communicating junctions

Occluding junctions (Tight junctions found only in vertebrates) fasten the adjacent epithelial sheets to avoid small molecules leakage from one side of the sheet to the other.

Anchoring junctions link the cytoskeleton of a cell to cytoskeleton of its neighbours or to the extracellular matrix. Main types of anchoring junctions in vertebrate tissues are Adherens junctions, Focal adhesions, Desmosomes and Hemidesmosomes. [1]

Gap junctions or communicating junctions are clusters of intercellular membrane channels that directly interact with the cytoplasm of adjoining cells. The topic of interest for this project is on Gap Junctions thus, the remainder of the discussion on this page will mainly be focused upon gap junctions.

Arrangement of connexins in gap junction.gif

In vertebrates, gap junction channels are composed of connexins, a large family of proteins containing approximately more than 20 members. Connexins (Cx) are named after their molecular weight and they are tissue-specific and even cell-specific which represent that some connexins are prominently expressed only in a few tissues and some, like Cx43 being more prevalent. [2] Six connexins oligomerize to form a connexon or hemichannel. [3] Connexons contain either a single type of connexin (homomeric) or several connexins (heteromeric). In addition, adjacent cells may comprise of identically or differently composed connexons hence forming a homotypic or heterotypic intercellular channels. [4]

The structure of gap junctions is to be discussed in detail after a brief history on gap junctions.

Functionally, gap junctions are important in generating electrical impulses in electrically excitable tissues such as heart, smooth muscle and some neurons. In non-excitable cells and other general aspects, they are reviewed to play a key role in electrical coupling and provide a pathway for sharing and selective exchange of metabolites. [5]

Likewise, the functional role of gap junctions will be elaborated further followed by the distribution of gap junctions in different tissues.

Following the discussion on location of gap junctions, a table comparing between different junctions will be constructed as a summary of information concerning various junctions.

Lastly, we will attempt to discuss some of the diseases that may be associated with the mutations or disruptions of different connexin genes and recent research with regard to gap junctions.


1959: Furshpan and Potter report that electrical stimulation that is insufficient to generate and action potential still allows current transfer between some nerve cells. [6]

1962: Dewey and Barr coin the term “nexus” to describe an intercellular connection between smooth muscle cells. [7] This term is now used interchangeably with the term “gap junction”

1963: Loewenstein and Kanno use microelectrodes and flurescent tracers to analyze the membrane permeability of epithelial cell junctions on Drosophilla salivary glands. They find that the junctional membrane surface is highly permeable so that small ions and fluorescent markers can move freely from one cell to the next.[8]

1963: Using thin slices of permanganate and osmium-fixed material, David Robinson discovers an array of hexagonal subunits in electrical synapses of Mauthner cells of goldfish. [9]

An Electron Micrograph of an Isolated Gap Junction (x 200,000)

1963-1967: Difference between gap junction and tight junction remains unclear and confusing.[10]

1967: Karnovsky and Revel use a lanthanum salt preparation on tissues to reveal the existence of hexagonal intercellular junctions in sections of mouse heart and mouse liver.[11] The lanthanum tracer penetrates a 2-3 nm gap between cell membranes for gap junctions, yet is not able to penetrate the firmly fused tight junctions.[12]

1970: Freeze cleaving electron microscopy techniques conducted by McNutt and Weinstein revealed that each of the two membranes which formed the gap junction could be split into lamellae, one neighbouring the cytoplasm, the other neighbouring the extracellular space.[13] Goodenough and Revel showed that the gap junction was characterized by 2 hexagonal subunits. [14]

1972: A method for isolating gap junctions from mouse liver using the detergent sarkosyl and X-ray diffraction is developed by Goodenough and Stoeckenius. [15]

1974: Connexin is chosen as the family name for the major gap junction proteins that were related but not identical in different tissues.[16]

1975: the term connexon is coined to describe a hexagonal subunit that spans the plasma membrane and forms half of the gap junction, along with a second connexon from an adjacent cell. [17]

1977: Crystallographic analysis of X-ray diffraction images make it possible to obtain a relatively detailed image of connexon structure. [18]

Micrograph of a negatively stained, isolated gap junction. (a) Low magnification view (x 90,000) of an isolated junction plaque about 0.7 pm across with hexagonal lattice extending throughout plaque. Higher magnification view (x 310,000) of this junction (b) shows that hexagonal packing of the unit is highly ordered with a lattice constant of about 85 A. Its optical diffraction pattern (c). Calculation of a filtered image of the junction (d) from the micrograph shows the average distribution stain about the connexons.

1979: Spray et al. show that gap junction channels in early amphibian embryos are voltage gated. [19]

Early 1980s: Development of ultra rapid freezing techniques allowed us to directly freeze cells and thus view gap junctions instantly at the moment of freezing.[20]

1983: Immunocytochemical localization is used to identify a specific type of gap junction protein. Anti 26K antibodies were localized to the liver gap junction protein (26K)[21].

1985: Manjunath and Page use optical diffraction with negatively stained isolated rabbit heart gap junctions to show six protein subunits of identical molecular weight forming the connexon. [22] These subunits each correspond to a connexin molecule. [23]

1986: Kumar and Gilula develop, clone, and characterize two recombinant cDNA probes coding for gap junction proteins, one for rat liver and one for human liver. [24] Different connexins continue to be discovered using cDNA clones from many tissues.[25] [26]

1987: At the Gap Junciton meeting held in Asilomar, scientists decide to adopt a nomenclature system for connexins which distinguishes connexins on the basis of species of origin and molecular mass in kiloDaltons. [27]

1991: Stauffer et. al develop a method involving cDNA which is able to isolate and purify intact connexons[28]

1995: 13 members of the connexin family in rodents have been identified. [29]

1995: The first connexin defect is described by Reaume et al. who observed that neonatal mice lacking connexin 43 suffered from cardiac malformation. [30] [31]

1997: Kelsell et al. identify a mutation in a gene encoding a the gap junction connexin protein connexin 26 which causes autosomal dominant deafness. [32]

1999: Unger et al. determine the structure of a recombinant cardiac gap junction using electron crystallography. [33]

2002: After screening both mouse and human genomic databases, Willecke et al. determine that there are 19 connexin genes in the mouse genome and 20 in the human genome. [34]

2004: New methodologies that use the activation of certain protein kinases show that phosphorylation of certain amino acids in the C terminal region of a connexin can lead to changes in gap junction communication, as well as regulate connexin trafficking, assembly, disassembly, degradation, and the opening and closing of the channel. [35]

Electron Micrograph Filtered Image of 2 Connexons

2005: Valiunas et al. show that short interfering RNAs (siRNA) can move from one cell to an adjacent cell via a gap junction if the correct connexin is a part of that particular gap junction. [36]

2006: Bugiani et al. demonstrate that mutations in the GJA12 gene which cause loss of function in connexin 47 cause Pelizaues-Merzbacher-like disease, a disease which manifests itself as a permanent lack of myelin deposition in the brain. [37]

2008: Mutations in the gene GJA1 which codes for connexin 43 can cause Oculodentodigital syndrome (ODD) which is characterized by abnormal development of the face, eyes, limbs, and teeth. Immunofluorescence analysis of adult tissues show that these areas affected by ODD are high in the expression on connexin 43. [38]

2010: The connexin gene family is made up of 20 genes in the mouse genome and 21 genes in the human genome. [39]

2010-2011: Research relating to gap junctions continues to exist, with over 1300 articles relating to gap junctions turning up on an April 22, 2011 Pubmed search for “gap junction”. [40]


Gap junctions are formed by two paired hemichannels, more commonly known as connexons, which come together to provide a direct connection between the cytoplasms of neighbouring cells. [41] [42] The two paired connexons come together to form a hydrophilic channel (1.5 nm diameter) between the two cytoplasms which allows for the passage of small molecules such as ions, second messengers, and small peptides between the two cells. [43] [44] [45]

Simple Cartoon Structure of Gap Junction.

These channels cluster together to form plaques of thousands of units.[46] In order for the two paired connexons to form a sealed channel, the two neighbouring cells must be brought extremely close together.[47] This forms a 2-4 nm intermembrane gap.[48] Each connexon is further made up of 6 protein molecules known as connexins. [49] Thus, a gap junction channel is made up of a total of 12 connexin molecules. In terms of molecular structure, a connexin folds into a four helix structure. [50] It is a transmembrane protein which spans the plasma membrane four times and has intracellular amino and carboxy terminal domains.[51]

A tangential section through a mouse heart reveals the hexagonal gap junctions.

Most cells express multiple types of connexins. These connexins can come together to form connexons that are either homomeric (made up of the same type connexin) or heteromeric (made up of multiple types of connexins). [52] [53] Furthermore, when two identical connexons join up, it is known as a homotypic channel. When two connexons made up of different connexins come together, it is known as a heterotypic channel. [54] Although many connexins are able to form heterotypic channels, not every single combination is permitted. Rather, whether or not a particular heterotypic channel is able to be formed depends on certain factors such as the expression of connexins in adjacent cells. [55] [56] The diversity in the different channels generated by the many different types of human connexins is important because it allows for the generation of different physiological properties, discussed in more detail in the “Function” section. [57]

As previously mentioned, there are currently 21 different connexin genes in the human genome. [58] The major differences in structure between these different connexin occur in the carboxyl terminal domain and the cytoplasmic loop. It is through these differences that we see specific regulatory properties in each connexin isoform. [59]

Schematic Diagram of Connexin 43. Note the four transmembrane domains, cytoplasmic and extracellular loops, and the N and C terminal domains. Red dots indicate location of mutations linked to the disease oculodentodigital dysplasia.

One connexin which will be discussed in further detail later in this page is connexin 43 (Cx43), the most expressed and abundant connexin in the human body.[60] Thus it is an appropriate connexin to use as an example for some of the universal structural features of connexin. Cx43, like its isoforms, has four transmembrane domains, two extracellular loops containing six conserved cysteine residues, a cytoplasmic loop, a cytoplasmic N terminal domain and a cytoplasmic C terminal domain. [61] [62] The carboxyl terminal domain of Cx43 is extremely important in chemically regulating gap junctions, since this is the region which becomes phosphorylated. [63] One study by Maass et al. found that the loss of this carboxyl terminal domain of Cx43 in the heart led to an increased susceptibility to arrhythmias, thus illustrating the importance of this structural domain. [64] However, it should be noted that connexins such as Cx36 and Cx56 can also be phosphorylated within the cytoplasmic loop. [65] Cx43, and all other connexins, are not phosphorylated in the N terminal domain. [66] Cx43’s cytoplasmic loop can interact with certain other connexins to form heteromeric channels. One example of this is that the Cx43 cytoplasmic loop can interact with the carboxyl terminal domain of Cx40. [67]

Cartoon Structure of Plasmodesmata. ER= Endoplasmic Reticulum, DM= Desmotubule, PM = Plasma Membrane, CW = Cell Wall.

While discussing the structure of gap junctions, it makes sense to briefly touch on their plant cellular counterpart known as plasmodesmata. They are similar to gap junctions in that they allow communication and ion exchange between neighbouring cells, yet differ in that, due to their larger diameter, they can pass larger molecules than gap junctions can. [68] The plasmodesmata also allow for the transport of signalling molecules such as non-cell autonomous proteins and RNA [69] In terms of structure, a plasmodesmata can be described as two cylinders which span the cell walls and connect the plasma membrane, cytoplasm, and endoplasmic reticulum of neighbouring cells. [70]

Plasmodesmata are approximately 40-50 nm in diameter. Running through the center of each of these intercellular channels is a dense rod known as the desmotubule, which helps stablize the plasmodesma structure and control its size. The desmotubule links the endoplasmic reticulums of neighbouring cells [71] Plasmodesmata can further be classified into primary and secondary. Primary plasmodesmata originate during cell division, while all other plasmodesmata, known as secondary, originate after cytokinesis. [72] Based on look, we can further classify plasmodesmata into simple, branched, or highly branched with central cavities. [73]

Functional role of gap junctions

Gap junction communication plays a principal role in maintaining cellular homeostasis by providing a pathway for exchanging small, hydrophilic molecules including glucose, glutathione, glutamate, cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP), inositol trisphosphate (IP3), and ions like calcium, sodium and potassium. [74]

The permeability of gap junctions depends on the composition of different connexin types. For instance, it was reviewed that Cx 43 channels are 120-160 fold more permeable to ADP and/or ATP than Cx 32 channels. Additionally, heterotypic gap junctions allow for special permeability characteristics compared to homotypic gap junctions. [75]

neocortex gap junctions

[76]Gap junction is also important for:

1) Transmission of excitation in cardiac muscle, smooth muscle and central nervous system (CNS) neurons;

2) Signalling in avascular and/or uninnervated tissues;

3) Control of cell growth and oncogenic transformation and

4) Regulation of early developmental events

The mechanisms of the functional role of gap junctions described above are explained further below.

Coupling through gap junctions in electrically excitable cells such as some nerve cells allow for the action potential to spread between the cells rapidly and accurately. Similarly, gap junctions in smooth muscle cells and cardiac muscle cells are responsible for peristaltic movement of the intestines and coordinating rhythmic contractions respectively. [77]

The signalling role of gap junctions can be exemplified in the liver. In normal physiological conditions, low levels of glucose in blood amount to the release of noradrenaline from the sympathetic nerve fibres which trigger the liver cells to break down glycogen and release glucose into the bloodstream. Neural stimulation of hepatocytes give rise to generation of signalling molecules such as inositol (1,4,5) -trisphosphate and release of Ca2+ from intracellular stores. However, hepatocytes at the venous end of the lobule are not directly innervated by sympathetic nerve fibres. Thus, gap junctions provide a pathway for those signalling molecules to be transported to uninnervated hepatocytes for glucose mobilization and release. [4]

Connexin 32 (Cx32) is highly expressed in hepatocytes and the review on the experiment concerning Cx32 knockout (KO) mice shows vulnerability to mutations and increase in incidence of hepatic tumors. The rate of cell growth was also remarkably increased in those Cx32 KO mice. These findings support the idea that inhibitory signals passing through intercellular channels of gap junctions may contribute to control of cell proliferation. Therefore, connexin genes of gap junctions might act as tumor suppressors. [4]

Gap junctions between oocyte and granulosa cells

The development of ovarian follicles and the production of fertile oocytes depend on gap junction mediated intercellular communication particularly between the oocyte and the surrounding granulosa cells. Cx37 containing gap junctions exist between the oocyte and the granulosa cells whereas granulosa cells are coupled to each other by Cx43 containing gap junctions. [78] The granulosa cells infer the loss of gap junction interaction between the oocyte and granulosa cells as equivalent to ovulation thus, granulosa cells start to luteinize. This may represent that in normal follicles, inhibitory signals are transmitted through gap junctions from the oocyte to granulosa cells to prevent luteinisation until ovulation has occurred. Thus, communication via gap junctions seems to offer bidirectional signalling system to regulate follicle growth, oogenesis, ovulation and luteinization. [4]

Gap junctions have various functions depending on different types and properties of connexins and their unique expressions, distributions and co-interactions with each other in different tissues. Hence, the role of gap junctions may not only be limited to aforementioned functions and can be explored further.


Gap junctions are composed of connexons. These connexons are located in almost all tissues except in sperm cells, red blood cells and skeletal muscle. In each location gap junctions provide a signalling pathway for neighbouring cells.[79]


Anatomy of the Heart

Gap junctions are located in the intercalated disks where they are involved in the electrical stimulation of the heart. Gap junctions are responsible for passing electrical impulses between cells creating a heart beat.[80]

Nervous System

The gap junction protein, connexin 32 is located in Schwann cells in the PNS and oligodendrocytes in the CNS. Connections are formed between neighbouring cells helping to control electric signals. Gap junction mutations lead to myelination defects.[81]

Smooth Muscle Cells

Connexin 43 and 40 are expressed in vascular smooth muscle where they have permeability and barrier properties. [82] Connexion 43 is a myometrial gap junction protein and it is increased prior to delivery. Gap junctions are important in communication leading to contractions of uterine smooth muscle cells during birth. [83]

Oocyte and follicular cells

Connexion 43 is located at the top of the oocyte and is important for oocyte development. Follicles lacking this connexin produce ineffective oocytes. The gap junctions are an important characteristic involved in folliculogenesis. [84]

Ear and Eye

Connexin 26 and connexin 30 form gap junctions in the cochlea, mutations in these proteins lead to human deafness. [85] Gap junctions are also found in the retina in amacrine and ganglion cells,specifically connexion 36 is involved in signal processing.[86]

Comparison with Other Junctions

Comparison of Cell Junctions
Name of Junction Function Location Associated Proteins Diseases Diagram
Tight Junction Tight junctions are the most apical junctions of epithelial cells and are important in sealing neighbouring cells together. They form a permeability barrier between individual cells controlling the transport of solutes, immune cells and drugs. Tight junctions also prevent the mixing of apical and basolateral components which help to maintain cell polarity.[87] Tight junctions are important in transcription, tumor suppression and cell proliferation.[88] Intestinal epithelial cells & endothelial cells [89] JAMs/Junctional Adhesion Molecules, occludin & claudins [90] Inflammatory Bowel Disease (IBD)

which includes Crohn's Disease and Ulcerative Colitis. These diseases are are associated with loss of the tight junction and alterations of tight junction proteins.[91]

Tight junction3.jpg

Adherens Junction

Adherens junctions are composed of a family of cadherin proteins. E-cadherin plays an important role in cell-cell adhesions and for the organisation of the intestinal epithelial barrier.[92] Adherens junctions control endothelial permeability via an opening and closing mechanism. Vascular endothelial cadherin, VE-cadherin, is responsible for epithelial integrity and for the maintenance of endothelial cells. It also controls cell proliferation, apoptosis and is important during embryonic angiogenesis.[93] Intestinal epithelial lining & Endothelial cells [94] Cadherins & Catenin[95] Crohn's Disease

Impaired E-cadherin in the small intestine and colon is associated with loss of homeostasis, barrier dysfunction and infections of enteropathogenic bacteria.[96]

Adherens Junctions structural proteins.png
Desmosomes Desmosomes are responsible for maintaining stable cell-cell adhesion and preserving mechanical strength.[97]

Desmosomes provide anchorage sites for intermediate filaments by attaching neighbouring cells together . They are responsible for barrier functions of the epidermis and mucous epithelia. Although desmosomes are critical for cell–cell adhesion, they contribute to morphogenesis and stabilising the tissue architecture.[98]

Found in cells subject to mechanical stress, such as the myocardium, bladder, gastrointestinal mucosa and skin.[99] Cadherins[100] Pemphigus & Bullous Impetigo

Desmosomes contain the desmogleins (Dsg) and desmocollins (Dsc). Pemphigus is an autoimmune disease of the skin and mucous membranes. Dsg1 and Dsg3 are two isoforms in the skin and mucous membranes which are targeted autoantibodies. Dsg1 is also targeted by a toxin which is released by Staphylococcus aureus in Bullous Impetigo leading to blistering.[101]

Hemidesmosome Epithelial cells use hemidesmosomes as way of attaching to the connective tissue[102]

Hemidesmosomes are responsible for attaching epithelial cells to the basement membrane which maintains cell integrity. Hemidesmosomes are involved in signal transduction and assist in the organisation of the cytoskeleton, apoptosis, and differentiation.[103]

skin, the cornea, parts of the gastrointestinal and respiratory tract[104] Integrin proteins[105] Epidermolysis Bullosa[106]

Defects in hemidesmosomal proteins can lead to blistering diseases of the skin.[107]

Cell adhesion summary.png
Neuromuscular Junction The neuromuscular junction is a synapse, which is an interaction formed between neurons or between a neuron and a specific cell. Communication occurs by neurotransmitter release from the presynaptic membrane which then activates receptors on the postsynaptic membrane. The NMJ uses different neurotransmitters in different organisms; in vertebrates, acetylcholine (ACh) causes excitation and muscle contraction. In others at excitatory NMJs, ACh causes muscle contraction, whereas at inhibitory NMJs GABA is released to cause muscle relaxation.[108] occurs between motor neurons and skeletal muscle fibres[109] Rapsyn [110] & Cortactin [111] Myasthenia Gravis

This is an autoimmune disorder where neuromuscular block occurs. This block is caused by a reduction in the response by the motor end plates to the transmitter, and as well a decrease in the number operating end plates, resulting in muscle fatigue.[112]

Lambert-Eaton Myasthenic Syndrome This disease is associated with defective neurotransmitter release in the neuromuscular junction resulting in impaired muscle function[113]

Detailed view of a neuromuscular junction:
1. Presynaptic terminal
2. Sarcolemma
3. Synaptic vesicle
4. Nicotinic acetylcholine receptor
5. Mitochondrion

Diseases Associated with Gap Junctions

Connexin function and expression may be altered by a variety of factors such as hormones and cytokines (for example, tumour necrosis factor-α) and lead to a disease state. However, one of the most important mechanisms that regulates gap junction function is the increase or decrease in the phosphorylation state of individual connexins by a variety of proteins. This leads to mutations in different connexin isoforms which are associated with a range of human diseases. [114]

Deafness/ Hearing Impairments

Cochlear Implant

Connexin Mutations: Cx26, 30, 31, 32, 43

Description: During normal reception of sound, potassium ions are circulated from sensory hair cells to the fibrocytes in the cochlea and back to endolymph via gap junctions, maintaining the potassium/sodium endolymph balance. Mutations of the connexins occlude the gap junction channels or prevent the normal assembly of the channels which block the spread of potassium ions through the junction. Recessive transmission is the most common inheritance, involving a single gene, DFNB1 which codes for connexins which are expressed in the cochlear. [115] [116]

Symptoms: Prelingual, bilateral, prevalently stable sensorineural defect ranging in severity from mild to profound, depending on the amino acid sequence of the mutation. As a result this can lead to profound deficits on speech and language development. In general, the hearing impairment does not progress. Cochlear implants are a common treatment option to treat patients with connexin mutation related hearing impairments. [117] [118]

Skin Disorders

Palmoplantar Keratoderma

Types: Erythrokeratodermia variabilis (EKV), palmoplantar keratoderma (PPK), Vohwinkel syndrome (VS) and hidrotic ectodermal dysplasia (HED)

Connexin Mutations: Cx26, 30, 31

Description: Cx26 in the epidermis plays an essential role in coordinating keratinocyte growth and differentiation. EKV: Autosomal dominant disease. Environmental factors trigger the formation of migratory red patches that regress and reappear. The disease is caused by a mutation on the 1p34-35 chromosome which alters the voltage-gating and pore formation of the gap junction. PPK: Involves a mutation on the GJB2 gene, which tends to lead to clinical manifestations involving the palms and soles. VS: a specific form of PPK, is caused by a mutation of the D66H allele of the Cx26 connexin. HED: autosomal dominant disease, caused by variations in the G11R and A88V alleles of the GJB6 gene which encodes Cx30. It is thought that this changes the voltage-gating properties of gap junctions. [119]

Symptoms: Generalized brown hyperkeratosis with sharply demarcated hyperkeratotic plaques most often on the neck, extensor surfaces of the arms and legs and the buttocks. Hyperkeratosis of the palms and soles, often associated with peeling. Band-like constriction of fingers that lead to autoamputation, alopecia and nail abnormalities. [120]

Cardiac Dysfunction

Idiopathic Cardiomyopathy

Connexin Mutations: Cx43, 40, 45

Description: Connexin expression in diseased human tissue is as a result of either structural remodeling, alteration in the distribution and organization of gap junctions or remodeling of the connexin expression, including changes in the amount and type of connexin present. This is thought to contribute to abnormal conduction and arrhythmogenesis in diseased hearts. Mutations also lead to ventricular hypertrophy and pulmonary artery stenosis. Laterality defects occur due to Cx43 mutations. The number of connexins per intercalated disks can also be reduced. [121]

Symptoms: less coordinated spontaneous beating, myocardial infarction, first-degree atrioventricular block with associated bundle branch block, hypoplastic left heart, atrioventral canal defects, hypertrophic cardiomyopathy and ischeamic heart disease. [122]

Dominant Zonular Pulverulent Cataract

Cataract Surgery

Connexin Mutations: Cx 46, 50

Description: An inherited, autosomal dominant disease caused by a missense mutation results in a substitution thought to be at codon 63 of Cx46. Mutations in the connexins cause a disruption in the homeostasis of oxygenation and hydration in the lens of the eye. Normal transparency of the lens is lost, leading to lens opacification. [123]

Symptoms: Lens opacities that have pulverized, dust-like appearance of the lens. Numerous powdery or punctuate opacities located in different developmental regions are evident. [124]

Oculodentodigital Dysplasia (ODDD)

complete complex syndactyly with two fingers

Connexin Mutation: Cx43

Description: An autosomal dominant syndrome associated with a mutation with the connexin Cx43, or GJA1 gene, located on chromosome 6q22-q23. The mutations can cause misassembly of channels or alter the gap junction channel conduction properties. This leads to craniofacial and limb dysmorphism and neurodegeneration.

Symptoms: Typical craniofacial abnormalities include a thin nose with small anterverted nares, brittle nails and hair which are slow growing, ophthalmic abnormalities including microcornea, glaucoma, optic atrophy. Mandibular overgrowth, cleft palate, teeth abnormalities such as enamel hypoplasia and early tooth loss are also common. Hand and foot abnormalities most often involve syndactyly of the fourth and fifth finger and the second to fourth toes. Neurological symptoms are frequent and include dysarthria, ataxia and spastic paraparesis. [125]

Charcot-Marie-Tooth Disease

Foot Deformity as a result of Charcot-Marie-Tooth Disease

Connexin Mutation: Cx32

Description: Hereditary heterogeneous disease which affects the motor and sensory nerves of the peripheral nervous system. Transmission of the disease caused by a connexin mutation is linked X-linked, being on the X chromosome. Myelin sheaths and/or axons of the peripheral nerves are affected through degeneration or abnormal development. This leads to a decrease in the efficiency and velocity of nerve conduction. The Cx32 mutations are missense, nonsense, frameshift or deletion. [126] [127]

Symptoms: Muscular atrophy of the 4 extremities, particularly foot deformities such as ‘cavus foot’, abnormal or altered gait (mostly have a high step), muscle weakness and wasting and sensory loss, frequently depressed tendon reflexes and abnormal electrophysiological testing. [128] [129]

Current Research

The main areas of current and future research regarding gap junctions are their involvement in disease. The research is aimed at understanding from the simplest individual gap junction proteins to the whole organism.


Heterotypic Gap Junctions between Two Neurons in the Drosophila Brain Are Critical for Memory. (2011)

Recent studies have identified a link between gap junctions and memory but the mechanism which it does this has not been clarified. This study aims to discover the process by which gap junctions contribute to memory function. RNA interferance-mediated knockdowns of specific regions in the anterior paired later and the dorsal paired medial neurone of Drosophila fly brains were analysed. These two neurones form gap junctions in a part of the brain that is responsible for learning and memory. Results show that with modifications to the Drosophila's RNA, the organisms' anesthesia-sensitive memory is dramatically impacted. A direct link between the anterior paired later and dorsal paired medial neurones can be established with memory formation. [130]

The clinical features of patients with the homozygous 235delC and the compound-heterozygous Y136X/G45E of the GJB2 mutations (Connexin 26) in cochlear implant recipients (2011)

Hayashi et al. aimed to investigate the proportion of patients with cochlear implants who had a 235 deletion C mutation on the GJB2 gene. The GJB2 gene codes for connxein 26, which is strongly associated with hearing. This mutation was found in 14.4% of the alleles, in different variations. All of the subjects had severe hearing loss, some of which had progressive hearing loss. All patients recorded better performance after having the cochlear implantation. Some complications were found in 4 alleles (2 patients). Poorer outcomes were suggested to be linked to brain function and unexpected complications. [131]

Regulation of Connexin 43 by Basic Fibroblast Growth Factor in the Bladder: Transcriptional and Behavioral Implications (2011)

The gap junction protein, connexin 43, is up-regulated in the overactivity of an obstructive bladder. Although there are numerous steps involved in the pathway from DNA to protein expression in individual tissue, transcriptional control is one of the most important steps in Cx43 protein regulation. Western blotting was used to analyse extracellular regulated kinases as well as connexin 43 in bladder proteins. Results lead to beleive that extracellular signal regulated kinase protein as well as connexin 43 could be potential theraputic targets for increased urinary frequency.[132]

Connexin 43 gene expression in male and female gonads of porcine offspring following in utero exposure to an anti-androgen, flutamide (2009)

Flutamide are anti-androgens, compounds which are capable of inhibiting the effects of androgens (male sex hormones). This study aims to investigate the effects of maternal exposure to flutamide on the expression of connexin 43 in testes and ovaries, particularly in piglets. Immunochemistry, Western Blotting and RT-PCR were the techniques used to perform this study. From the evidence shown, there were no obvious changes in either the testes or ovarian morphology with connexin 43 being present in all the tissues examined. Androgens were therefore not believed to be involved int eh control of connexin 43 in the genetic expression of gonads in piglets. [133]


Amacrine Cells: Interneurons in the retina

Arrhythmogenesis: Conditions in which there is abnormal electrical activity in the heart.

Autoamputation: A spontaneous detachment from the body.

Autosome: A chromosome that is not a sex chromosome.

Connexin: Gap junction proteins, structurally-related transmembrane proteins that assemble to form vertebrate gap junctions

Connexon: An assembly of six proteins (connexins) that form gap junctions.

Dysmorphism: Any malformation which is suggestive of a congenital disorder, genetic syndrome, or birth defect.

Electrophysiological: Electrical results produced through physiological work, or by change of action in a living organism.

Folliculogenesis: Maturation of the ovarian follicle

Heteromeric: Multiple types of connexion

Heterotypic: Adjacent cells consisting of differently composed connexons

Homomeric: A single type of connexin

Homotypic: Adjacent cells consisting of identically composed connexons

Intercalated Disc:: Transversely oriented bands throughout cardiac muscle

Laterality: Localization of greater function in either the right or left side of the body.

Neurotransmitter: Chemicals which allow the transmission of signals from one neuron to another neuron

Opacification: The process of becoming opaque/cloudy.

Syndactyly: A condition where 2 or more of the digits are fused together (partially or totally).


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2011 Projects: Synaptic Junctions | Gap Junctions | Tight Junctions | Desmosomes | Adherens Junctions | Neuromuscular Junction