GJB6

{{Short description|Protein-coding gene in the species Homo sapiens}}

Gap junction beta-6 protein (GJB6), also known as connexin 30 (Cx30) — is a protein that in humans is encoded by the GJB6 gene.{{cite journal | vauthors = Grifa A, Wagner CA, D'Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, Rabionet R, Arbones M, Monica MD, Estivill X, Zelante L, Lang F, Gasparini P | title = Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus | journal = Nature Genetics | volume = 23 | issue = 1 | pages = 16–18 | date = September 1999 | pmid = 10471490 | doi = 10.1038/12612 | s2cid = 29044968 }}{{cite journal | vauthors = Kibar Z, Der Kaloustian VM, Brais B, Hani V, Fraser FC, Rouleau GA | title = The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q | journal = Human Molecular Genetics | volume = 5 | issue = 4 | pages = 543–547 | date = April 1996 | pmid = 8845850 | doi = 10.1093/hmg/5.4.543 | doi-access = free }}{{cite web | title = Entrez Gene: GJB6 gap junction protein, beta 6| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10804 }} Connexin 30 (Cx30) is one of several gap junction proteins expressed in the inner ear.{{cite journal | vauthors = Zhao HB, Kikuchi T, Ngezahayo A, White TW | title = Gap junctions and cochlear homeostasis | journal = The Journal of Membrane Biology | volume = 209 | issue = 2–3 | pages = 177–186 | year = 2006 | pmid = 16773501 | pmc = 1609193 | doi = 10.1007/s00232-005-0832-x }} Mutations in gap junction genes have been found to lead to both syndromic and nonsyndromic deafness.{{cite journal | vauthors = Erbe CB, Harris KC, Runge-Samuelson CL, Flanary VA, Wackym PA | title = Connexin 26 and connexin 30 mutations in children with nonsyndromic hearing loss | journal = The Laryngoscope | volume = 114 | issue = 4 | pages = 607–611 | date = April 2004 | pmid = 15064611 | doi = 10.1097/00005537-200404000-00003 | s2cid = 25847431 }} Mutations in this gene are associated with Clouston syndrome (i.e., hydrotic ectodermal dysplasia).

Function

The connexin gene family codes for the protein subunits of gap junction channels that mediate direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. Connexins span the plasma membrane 4 times, with amino- and carboxy-terminal regions facing the cytoplasm. Connexin genes are expressed in a cell type-specific manner with overlapping specificity. The gap junction channels have unique properties depending on the type of connexins constituting the channel.[supplied by OMIM]

Connexin 30 is prevalent in the two distinct gap junction systems found in the cochlea: the epithelial cell gap junction network, which couple non-sensory epithelial cells, and the connective tissue gap junction network, which couple connective tissue cells. Gap junctions serve the important purpose of recycling potassium ions that pass through hair cells during mechanotransduction back to the endolymph.{{cite journal | vauthors = Kikuchi T, Kimura RS, Paul DL, Takasaka T, Adams JC | title = Gap junction systems in the mammalian cochlea | journal = Brain Research. Brain Research Reviews | volume = 32 | issue = 1 | pages = 163–166 | date = April 2000 | pmid = 10751665 | doi = 10.1016/S0165-0173(99)00076-4 | s2cid = 11292387 }}

Connexin 30 has been found to be co-localized with connexin 26.{{cite journal | vauthors = Lautermann J, ten Cate WJ, Altenhoff P, Grümmer R, Traub O, Frank H, Jahnke K, Winterhager E | title = Expression of the gap-junction connexins 26 and 30 in the rat cochlea | journal = Cell and Tissue Research | volume = 294 | issue = 3 | pages = 415–420 | date = December 1998 | pmid = 9799458 | doi = 10.1007/s004410051192 | s2cid = 24537527 }} Cx30 and Cx26 have also been found to form heteromeric and heterotypic channels. The biochemical properties and channel permeabilities of these more complex channels differ from homotypic Cx30 or Cx26 channels.{{cite journal | vauthors = Yum SW, Zhang J, Valiunas V, Kanaporis G, Brink PR, White TW, Scherer SS | title = Human connexin26 and connexin30 form functional heteromeric and heterotypic channels | journal = American Journal of Physiology. Cell Physiology | volume = 293 | issue = 3 | pages = C1032–C1048 | date = September 2007 | pmid = 17615163 | doi = 10.1152/ajpcell.00011.2007 | s2cid = 16854059 }} Overexpression of Cx30 in Cx30 null mice restored Cx26 expression and normal gap junction channel functioning and calcium signaling, but it is described that Cx26 expression is altered in Cx30 null mice. The researchers hypothesized that co-regulation of Cx26 and Cx30 is dependent on phospholipase C signaling and the NF-κB pathway.{{cite journal | vauthors = Ortolano S, Di Pasquale G, Crispino G, Anselmi F, Mammano F, Chiorini JA | title = Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 48 | pages = 18776–18781 | date = December 2008 | pmid = 19047647 | pmc = 2596232 | doi = 10.1073/pnas.0800831105 | doi-access = free | bibcode = 2008PNAS..10518776O }}

The cochlea contains two cell types, auditory hair cells for mechanotransduction and supporting cells. Gap junction channels are only found between cochlear supporting cells.{{cite journal | vauthors = Kikuchi T, Kimura RS, Paul DL, Adams JC | title = Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis | journal = Anatomy and Embryology | volume = 191 | issue = 2 | pages = 101–118 | date = February 1995 | pmid = 7726389 | doi = 10.1007/BF00186783 | s2cid = 24900775 }} While gap junctions in the inner ear are critically involved in potassium recycling to the endolymph, connexin expression in the supporting cells surrounding the organ of Corti have been found to support epithelial tissue lesion repair following loss of sensory hair cells. An experiment with Cx30 null mice found deficits in lesion closure and repair of the organ of Corti following hair cell loss, suggesting that Cx30 has a role in regulating lesion repair response.{{cite journal | vauthors = Forge A, Jagger DJ, Kelly JJ, Taylor RR | title = Connexin30-mediated intercellular communication plays an essential role in epithelial repair in the cochlea | journal = Journal of Cell Science | volume = 126 | issue = Pt 7 | pages = 1703–1712 | date = April 2013 | pmid = 23424196 | doi = 10.1242/jcs.125476 | doi-access = free }}

Astrocytes play a crucial role in synaptic physiology and information processing in the brain. A key characteristic of astrocytes is their expression of Cx30, which influences cognitive processes by shaping synaptic and network activities. This Cx-mediated astroglial network regulates the efficiency of extracellular potassium (K+) and glutamate clearance at synapses,{{cite journal | vauthors = Pannasch U, Vargová L, Reingruber J, Ezan P, Holcman D, Giaume C, Syková E, Rouach N | title = Astroglial networks scale synaptic activity and plasticity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 20 | pages = 8467–8472 | date = May 2011 | pmid = 21536893 | pmc = 3100942 | doi = 10.1073/pnas.1016650108 | doi-access = free | bibcode = 2011PNAS..108.8467P }} as well as the long-distance trafficking of energy metabolites to fuel active synapses.{{cite journal | vauthors = Pannasch U, Vargová L, Reingruber J, Ezan P, Holcman D, Giaume C, Syková E, Rouach N | title = Astroglial networks scale synaptic activity and plasticity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 20 | pages = 8467–8472 | date = May 2011 | pmid = 21536893 | pmc = 3100942 | doi = 10.1073/pnas.1016650108 | doi-access = free | bibcode = 2011PNAS..108.8467P }}{{cite journal | vauthors = Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C | title = Astroglial metabolic networks sustain hippocampal synaptic transmission | journal = Science | volume = 322 | issue = 5907 | pages = 1551–1555 | date = December 2008 | pmid = 19056987 | doi = 10.1126/science.1164022 | bibcode = 2008Sci...322.1551R }} However, Cxs do not only form gap junction channels with other astrocytes; they can also mediate direct exchange with the extracellular space when forming hemichannels.{{cite journal | vauthors = Chever O, Lee CY, Rouach N | title = Astroglial connexin43 hemichannels tune basal excitatory synaptic transmission | journal = The Journal of Neuroscience | volume = 34 | issue = 34 | pages = 11228–11232 | date = August 2014 | pmid = 25143604 | pmc = 6615508 | doi = 10.1523/JNEUROSCI.0015-14.2014 }}

Cx30 protein levels set the size of astrocytic networks, and can be modulated by neuronal activity, indicating a close relationship between astrocytic network size and the activation of underlying neuronal networks. However, this modulation is complex, as it differentially impacts principal cells and interneurons.{{cite journal | vauthors = Hardy E, Cohen-Salmon M, Rouach N, Rancillac A | title = Astroglial Cx30 differentially impacts synaptic activity from hippocampal principal cells and interneurons | journal = Glia | volume = 69 | issue = 9 | pages = 2178–2198 | date = September 2021 | pmid = 33973274 | doi = 10.1002/glia.24017 | url = https://inserm.hal.science/inserm-03207590v3/file/ACDIS.pdf | quote = Cx30 alters specific properties of certain subsets of CA1 interneurons, such as resting membrane potential and sag ratio, while other parameters, such as action potential threshold and saturation frequency, were more frequently altered across different classes of neurons. The excitation-inhibition balance was also differentially and selectively modulated among the various neuron subtypes. Therefore, astrocytes, via Cx30, actively modulate both excitatory and inhibitory synapses in the hippocampus. }} Additionally, Cx30 can also act via other mechanisms, such as signaling and protein interactions. Recent research has shown that the increase in Cx30 levels between P10 to P50 controls the closure of the critical period in the mouse visual cortex through a signaling pathway that regulates the extracellular matrix and interneuron maturation.{{cite journal | vauthors = Ribot J, Breton R, Calvo CF, Moulard J, Ezan P, Zapata J, Samama K, Moreau M, Bemelmans AP, Sabatet V, Dingli F, Loew D, Milleret C, Billuart P, Dallérac G, Rouach N | title = Astrocytes close the mouse critical period for visual plasticity | journal = Science | volume = 373 | issue = 6550 | pages = 77–81 | date = July 2021 | pmid = 34210880 | doi = 10.1126/science.abf5273 | bibcode = 2021Sci...373...77R }}

In the hippocampus, decreased Cx30 expression reduces the size of astroglial networks, while upregulation of Cx30 increases their size.{{cite journal | vauthors = Hardy E, Moulard J, Walter A, Ezan P, Bemelmans AP, Mouthon F, Charvériat M, Rouach N, Rancillac A | title = Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory | journal = PLOS Biology | volume = 21 | issue = 4 | pages = e3002075 | date = April 2023 | pmid = 37040348 | pmc = 10089355 | doi = 10.1371/journal.pbio.3002075 | editor-first = Cagla | doi-access = free | editor-last = Eroglu }} In both cases, it decreases spontaneous and evoked synaptic transmission. This effect results from reduced neuronal excitability, leading to alterations in the induction of synaptic plasticity and impairments in learning processes in vivo. Altogether, this suggest that astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.

Clinical significance

= Auditory =

Connexin 26 and connexin 30 are commonly accepted to be the predominant gap junction proteins in the cochlea. Genetic knockout experiments in mice has shown that knockout of either Cx26 or Cx30 produces deafness.{{cite journal | vauthors = Teubner B, Michel V, Pesch J, Lautermann J, Cohen-Salmon M, Söhl G, Jahnke K, Winterhager E, Herberhold C, Hardelin JP, Petit C, Willecke K | title = Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential | journal = Human Molecular Genetics | volume = 12 | issue = 1 | pages = 13–21 | date = January 2003 | pmid = 12490528 | doi = 10.1093/hmg/ddg001 | doi-access = free }}{{cite journal | vauthors = Kudo T, Kure S, Ikeda K, Xia AP, Katori Y, Suzuki M, Kojima K, Ichinohe A, Suzuki Y, Aoki Y, Kobayashi T, Matsubara Y | title = Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness | journal = Human Molecular Genetics | volume = 12 | issue = 9 | pages = 995–1004 | date = May 2003 | pmid = 12700168 | doi = 10.1093/hmg/ddg116 | doi-access = free }} However, recent research suggests that Cx30 knockout produces deafness due to subsequent downregulation of Cx26, and one mouse study found that a Cx30 mutation that preserves half of Cx26 expression found in normal Cx30 mice resulted in unimpaired hearing.{{cite journal | vauthors = Boulay AC, del Castillo FJ, Giraudet F, Hamard G, Giaume C, Petit C, Avan P, Cohen-Salmon M | title = Hearing is normal without connexin30 | journal = The Journal of Neuroscience | volume = 33 | issue = 2 | pages = 430–434 | date = January 2013 | pmid = 23303923 | pmc = 6704917 | doi = 10.1523/JNEUROSCI.4240-12.2013 | doi-access = free }} The lessened severity of Cx30 knockout in comparison to Cx26 knockout is supported by a study examining the time course and patterns of hair cell degeneration in the cochlea. Cx26 null mice displayed more rapid and widespread cell death than Cx30 null mice. The percent hair cell loss was less widespread and frequent in the cochleas of Cx30 null mice.{{cite journal | vauthors = Sun Y, Tang W, Chang Q, Wang Y, Kong W, Lin X | title = Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea | journal = The Journal of Comparative Neurology | volume = 516 | issue = 6 | pages = 569–579 | date = October 2009 | pmid = 19673007 | pmc = 2846422 | doi = 10.1002/cne.22117 }}

= Sleep cycle =

Connexin 30 (Cx30) appears to play a crucial role in regulating sleep and wakefulness, potentially through its involvement in circadian rhythm generation, response to sleep pressure, and modulation of astrocyte morphology and function.

Research has shown that Cx30 and Connexin 43 (Cx43) exhibit a time-of-day dependent expression in the mouse suprachiasmatic nucleus (SCN), the central circadian rhythm generator. These connexins contribute to the electric coupling of SCN neurons and astrocytic-neuronal signaling that regulates rhythmic SCN neuronal activity.

Interestingly, the fluctuation of Cx30 protein expression strongly depends on the light-dark cycle, which suggests that Cx30 may play a role in the circadian system's light entrainment and circadian rhythm generation.

In a study using Cx30 knockout mice, researchers have found that these mice exhibited a deficit in maintaining wakefulness during periods of high sleep pressure. They needed more stimuli to stay awake during gentle sleep deprivation and showed increased slow-wave sleep during instrumental sleep deprivation.

Moreover, neuronal activity has been found to increase hippocampal Cx30 protein levels via a posttranslational mechanism regulating lysosomal degradation, which translated at the functional level in the activation of Cx30 hemichannels and in Cx30-mediated remodeling of astrocyte morphology independently of gap junction biochemical coupling.

The clinical significance of this finding is that it can explain the mechanism of action of modafinil in its wakefulness-promoting properties.{{cite journal | vauthors = Thorpy MJ, Bogan RK | title = Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications | journal = Sleep Medicine | volume = 68 | issue = | pages = 97–109 | date = April 2020 | pmid = 32032921 | doi = 10.1016/j.sleep.2019.09.001 | s2cid = 203405397 }} Modafinil may promote wakefulness by modulating the function of astroglial connexins, specifically connexin 30, which are proteins that facilitate intercellular communication and play a role in sleep-wake regulation.{{cite journal | vauthors = Que M, Li Y, Wang X, Zhan G, Luo X, Zhou Z | title = Role of astrocytes in sleep deprivation: accomplices, resisters, or bystanders? | journal = Frontiers in Cellular Neuroscience | volume = 17 | issue = | pages = 1188306 | date = 2023 | pmid = 37435045 | pmc = 10330732 | doi = 10.3389/fncel.2023.1188306 | doi-access = free }}{{cite journal | vauthors = Ingiosi AM, Frank MG | title = Goodnight, astrocyte: waking up to astroglial mechanisms in sleep | journal = The FEBS Journal | volume = 290 | issue = 10 | pages = 2553–2564 | date = May 2023 | pmid = 35271767 | pmc = 9463397 | doi = 10.1111/febs.16424 }}{{cite journal | vauthors = Thorpy MJ | title = Recently Approved and Upcoming Treatments for Narcolepsy | journal = CNS Drugs | volume = 34 | issue = 1 | pages = 9–27 | date = January 2020 | pmid = 31953791 | pmc = 6982634 | doi = 10.1007/s40263-019-00689-1 }} Connexins form channels that allow the exchange of ions and signaling molecules between cells. In the brain, they are mainly expressed by astrocytes, which help regulate neuronal activity.{{cite journal | vauthors = Yang S, Kong XY, Hu T, Ge YJ, Li XY, Chen JT, He S, Zhang P, Chen GH | title = Aquaporin-4, Connexin-30, and Connexin-43 as Biomarkers for Decreased Objective Sleep Quality and/or Cognition Dysfunction in Patients With Chronic Insomnia Disorder | journal = Frontiers in Psychiatry | volume = 13 | issue = | pages = 856867 | date = 2022 | pmid = 35401278 | pmc = 8989729 | doi = 10.3389/fpsyt.2022.856867 | doi-access = free }} Modafinil increases the levels of connexin 30 in the cortex, enhancing communication between astrocytes and promoting wakefulness. Conversely, connexin 30 levels decrease during sleep, contributing to the transition from wakefulness to sleep. Flecainide, a drug that blocks astroglial connexins, can enhance the effects of modafinil on wakefulness and cognition, and reduce narcoleptic episodes in animal models. These findings suggest that modafinil may exert its therapeutic effects by modulating astroglial connexins.

References

External links

{{OMIM|604418|Gap Junction Protein, BETA-6; GJB6}}
{{OMIM|148210|Keratitis-Ichthyosis-Deafness Syndrome, Autosomal Dominant}}
{{OMIM|601544|Deafness, Autosomal Dominant 3A; DFNA3A}}
{{OMIM|129500|Clouston Syndrome}}
{{OMIM|220290|Deafness, Autosomal Recessive 1A; DFNB1A}}

Category:Connexins