Editing Gap junction (section)

===Areas of electrical coupling===
Gap junctions electrically couple cells throughout the body of most animals. Electrical coupling can be relatively fast acting and can be used over short distances within an organism. Tissues in this section have well known functions observed to be coordinated by gap junctions, with intercellular signaling happening in time frames of microseconds or less.

====Heart====
[[File:Perinexial ephaptic coupling.jpg|thumb|Effects of perinexal width on ephaptic coupling, for G gap = 0 nS]]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 unison. The importance is emphasized by a secondary [[Ephaptic coupling|ephaptic pathway]] for the signal to contract also being associated with the gap junction plaques. This redundancy in signal transmission associated with gap junction plaques is the first to be described and involves sodium channels rather than connexins.<ref name="Localization of Na + channel cluste"/><ref>{{cite journal |last1=Ivanovic |first1=Ena |last2=Kucera |first2=Jan P. |title=Tortuous Cardiac Intercalated Discs Modulate Ephaptic Coupling |journal=Cells |date=2 November 2022 |volume=11 |issue=21 |pages=3477 |doi=10.3390/cells11213477|doi-access=free |pmid=36359872 |pmc=9655400 }}</ref>

====Eye lens====
[[File:Lens3Dmap with txt.jpg|thumb|Eye lens showing arrangement of fiber cells with photos of gap junction plaques from different regions]]Precise control of light refraction, structural dimensions and transparency are key aspects of the eye lens structure that allow focusing by the eye. Transparency is aided by the absence of nerves and blood vessels from the lens, so gap junctions are left with a larger loading of intercellular communication than in other tissues reflected in large numbers of gap junctions. The [[crystallinity]] of the lens also means the cells and gap junctions are well ordered for systematic mapping of where the gap junction plaques are. As no cells are lost from the lens interior during the life of the animal, a complete map of the gap junctions is possible.<ref name = Gruijters>{{cite journal |last1=Gruijters |first1=W.T. |last2=Kistler |first2=J. |last3=Bullivant |first3=S. |title=Formation, distribution and dissociation of intercellular junctions in the lens |journal=Journal of Cell Science |date=1 October 1987 |volume=88 |issue=3 |pages=351–359 |doi=10.1242/jcs.88.3.351|pmid=3448099 }}</ref>

The associated figure shows how the size, shape, and frequency of gap junction plaques change with cell growth. With growth, fiber cells are progressively isolated from more direct metabolite exchange with the [[Aqueous humour|aqueous humor]] through the capsule and lens epithelium. The isolation correlates with the classical circular shape of larger plaques shown in the yellow zone being disrupted. Changing the fiber cells' morphology requires the movements of vesicles through the gap junction plaques at higher frequencies in this area.<ref name="Gruijters-vesicles">{{cite journal |last1=Gruijters |first1=W |title=Are gap junction membrane plaques implicated in intercellular vesicle transfer? |journal=Cell Biology International |date=2003 |volume=27 |issue=9 |pages=711–717 |doi=10.1186/s12862-019-1369-4|pmid=30813901 |pmc=6391747 |doi-access=free |bibcode=2019BMCEE..19S..46S }}</ref>

====Neurons====
A gap junction located between neurons is often referred to as an [[electrical synapse]]. The electrical synapse was discovered using electrical measurements before the gap junction structure was described. In mammals, electrical synapses are present throughout the central nervous system and have been studied specifically in the [[neocortex]], [[hippocampus]], [[vestibular nucleus]], [[thalamic reticular nucleus]], [[locus coeruleus]], [[inferior olivary nucleus]], mesencephalic nucleus of the [[trigeminal nerve]], [[ventral tegmental area]], [[olfactory bulb]], [[retina]] and [[spinal cord]] of [[vertebrate]]s.<ref>{{cite journal | last1 = Connors | last2 = Long | year = 2004 | title = Electrical synapses in the mammalian brain | url = https://zenodo.org/record/894386| journal = Annu Rev Neurosci | volume = 27 | pages = 393–418 | doi=10.1146/annurev.neuro.26.041002.131128 | pmid=15217338}}<!--https://zenodo.org/record/894386--></ref>  In invertibrates, gap gunctions are known to be expressed widely in the brain of the fruit fly, ''Drosophila''.<ref name="Ammer">{{cite journal 
  |title=Anatomical distribution and functional roles of electrical synapses in Drosophila
  |last1=Ammer |first1=Georg |last2=Vieira |first2=Renee M |last3=Fendl |first3=Sandra |last4=Borst |first4=Alexander
  |journal=Current Biology
  |volume=32
  |issue=9
  |year=2022
  |pages=2022–2036.e4 |publisher=Elsevier|doi=10.1016/j.cub.2022.03.040 |pmid=35385694 |bibcode=2022CBio...32E2022A }}</ref>

There has been some observation of coupling in the [[locus coeruleus]] between weak neurons and [[glial cell]]s and in the [[cerebellum]] between [[Purkinje neuron]]s and [[Bergmann glial cell]]s. It appears that [[astrocyte]]s are coupled by gap junctions, both to other astrocytes and to [[oligodendrocyte]]s.<ref>{{cite journal|last=Orthmann-Murphy|first=Jennifer L.|author2=Abrams, Charles K. |author3=Scherer, Steven S. |title=Gap Junctions Couple Astrocytes and Oligodendrocytes|journal=Journal of Molecular Neuroscience|date=May 2008|volume=35|issue=1|pages=101–116|doi=10.1007/s12031-007-9027-5|pmid=18236012 |pmc=2650399}}</ref> 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 neuronal gap junctions include m[[GJD2|CX36]], mCX57, and m[[GJC1|CX45]], with mRNAs for at least five other connexins (m[[GJB2|Cx26]], m[[GJC3|Cx30.2]], m[[GJB1|Cx32]], m[[GJA1|Cx43]], m[[GJC2|Cx47]]) detected but without immunocytochemical evidence for the corresponding protein within ultrastructurally-defined gap junctions. Those mRNAs appear to be downregulated or destroyed by micro interfering RNAs ([[miRNA]]s) that are cell-type and cell-lineage specific.

Within the brain of the fruit fly ''Drosophila'', gap junctions are known to be critical for a variety of functions.<ref>{{cite journal 
  |title=Heterotypic gap junctions between two neurons in the Drosophila brain are critical for memory
  |last1= Wu |first1= Chia-Lin |last2= Shih |first2= Meng-Fu Maxwell |last3= Lai |first3= Jason Sih-Yu
  |last4= Yang |first4= Hsun-Ti |last5= Turner |first5= Glenn C |last6= Chen |first6= Linyi
  |last7= Chiang |first7= Ann-Shyn
  |journal=Current Biology
  |volume=21
  |issue=10
  |pages=848–854
  |year=2011
  |publisher=Elsevier  |doi= 10.1016/j.cub.2011.02.041 |pmid= 21530256 |bibcode= 2011CBio...21..848W }}</ref>
<ref name="Ammer"/>
<ref>{{cite journal 
  |title=Gap junction networks in mushroom bodies participate in visual learning and memory in Drosophila
  |last1=Liu |first1=Qingqing |last2=Yang |first2=Xing |last3=Tian |first3=Jingsong  |last4=Gao |first4=Zhongbao
  |last5=Wang |first5=Meng |last6=Li |first6=Yan |last7=Guo |first7=Aike
  |journal=eLife
  |volume=5
  |pages=e13238
  |year=2016
  |url=https://elifesciences.org/articles/13238.pdf
  |publisher=eLife Sciences Publications, Ltd |doi=10.7554/eLife.13238 |doi-access=free |pmid=27218450 |pmc=4909397 }}</ref>

'''Astrocytes'''

An important feature of astrocytes is their high expression levels of the gap junction proteins [[connexin 30]] (Cx30) and [[connexin 43]] (Cx43). These proteins play crucial roles in regulating brain homeostasis through potassium buffering, intercellular communication, and nutrient transport. <ref>{{Cite journal |last1=Pannasch |first1=Ulrike |last2=Vargová |first2=Lydia |last3=Reingruber |first3=Jürgen |last4=Ezan |first4=Pascal |last5=Holcman |first5=David |last6=Giaume |first6=Christian |last7=Syková |first7=Eva |last8=Rouach |first8=Nathalie |date=2011-05-17 |title=Astroglial networks scale synaptic activity and plasticity |journal=Proceedings of the National Academy of Sciences |language=en |volume=108 |issue=20 |pages=8467–8472 |doi=10.1073/pnas.1016650108 |doi-access=free |issn=0027-8424 |pmc=3100942 |pmid=21536893|bibcode=2011PNAS..108.8467P }}</ref> Connexins typically form gap junction channels that allow direct intercellular communication between astrocytes. However, they can also form hemichannels that facilitate the exchange of ions and molecules with the extracellular space.

Studies have highlighted channel-independent functions of connexins, involving intracellular signaling, protein interactions, and cell adhesion. <ref>{{Cite journal |last1=Ghézali |first1=Grégory |last2=Dallérac |first2=Glenn |last3=Rouach |first3=Nathalie |date=2016 |title=Perisynaptic astroglial processes: dynamic processors of neuronal information |url=http://link.springer.com/10.1007/s00429-015-1070-3 |journal=Brain Structure and Function |language=en |volume=221 |issue=5 |pages=2427–2442 |doi=10.1007/s00429-015-1070-3 |pmid=26026482 |issn=1863-2653}}</ref> Specifically, Cx30 has been shown to regulate the insertion of astroglial processes into synaptic clefts, which controls the efficacy of glutamate clearance. This, in turn, affects the synaptic strength and long-term plasticity of excitatory terminals, indicating a significant role in modulating synaptic transmission. Levels of Cx30 regulate synaptic glutamate concentration, hippocampal excitatory synaptic strength, plasticity, and memory. Astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.<ref>{{Cite journal |last1=Hardy |first1=Eléonore |last2=Moulard |first2=Julien |last3=Walter |first3=Augustin |last4=Ezan |first4=Pascal |last5=Bemelmans |first5=Alexis-Pierre |last6=Mouthon |first6=Franck |last7=Charvériat |first7=Mathieu |last8=Rouach |first8=Nathalie |last9=Rancillac |first9=Armelle |date=2023-04-11 |editor-last=Eroglu |editor-first=Cagla |title=Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory |journal=PLOS Biology |language=en |volume=21 |issue=4 |pages=e3002075 |doi=10.1371/journal.pbio.3002075 |doi-access=free |issn=1545-7885 |pmc=10089355 |pmid=37040348 |quote=Cx30 upregulation increases the connectivity of astroglial networks, it decreases spontaneous and evoked synaptic transmission. This effect results from a reduced neuronal excitability and translates into an alteration in the induction of synaptic plasticity and an in vivo impairment in learning processes. Altogether, these results suggest that astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.}}</ref>

Cx30 is not limited to regulating excitatory synaptic transmission but also plays a crucial role in inhibitory synaptic regulation and broader neuronal network activities.<ref>{{Cite journal |last1=Hardy |first1=Eléonore |last2=Cohen-Salmon |first2=Martine |last3=Rouach |first3=Nathalie |last4=Rancillac |first4=Armelle |date=September 2021 |title=Astroglial Cx30 differentially impacts synaptic activity from hippocampal principal cells and interneurons |url=https://onlinelibrary.wiley.com/doi/10.1002/glia.24017 |journal=Glia |language=en |volume=69 |issue=9 |pages=2178–2198 |doi=10.1002/glia.24017 |pmid=33973274 |issn=0894-1491 |quote=Cx30 differentially alters the electrophysiological and morphological properties of hippocampal cell populations. They modulates both excitatory and inhibitory inputs. Astrocytes, via Cx30, are thus active modulators of both excitatory and inhibitory synapses in the hippocampus.}}</ref> This highlights the importance of connexins in maintaining the intricate balance required for proper brain function.

====Retina====
Neurons within the [[retina]] show extensive coupling, both within populations of one cell type and between different cell types.<ref>{{cite journal |author1=Béla Völgyi |author2=Stewart A. Bloomfield |title=The diverse functional roles and regulation of neuronal gap junctions in the retina |journal=Nature Reviews Neuroscience |date=February 2009| volume=10 |issue=7 |pages=495–506| doi=10.1016/S0165-0173(99)00070-3 |pmid=19491906 |pmc=3381350}}</ref>

====Uterus====
The [[Uterus|uterine]] muscle ([[myometrium]]) remains in a quiescent relaxed state during [[pregnancy]] to maintain [[fetal development]]. Immediately preceding [[Childbirth|labor]], the myometrium transforms into an activated contractile unit by increasing expression of [[GJA1|connexin-43]] ([[Cx43|CX43]], a.k.a. Gap Junction Alpha-1 protein, [[GJA1]]) facilitating gap junction (GJ) formation between individual myometrial cells. Importantly, the formation of GJs promotes communication between neighbouring [[Muscle cell|myocytes]], which facilitates the transfer of small molecules such as secondary messengers, metabolites, and small ions for electrical coupling. Consistent with all species, uterine myometrial contractions propagate from spontaneous [[action potential]]s as a result of sudden change in [[Cell membrane|plasma membrane]] permeability. This leads to an increase of intracellular [[Ca²⁺]] concentration, facilitating action potential propagation through electrically coupled cells.<ref>Garfield, RE; Sims, SM; Kannan, MS; Daniel, EE (November 1978). "Possible role of gap junctions in activation of myometrium during parturition". ''Am. J. Physiol''. '''235''' (5): C168–79. [https://journals.physiology.org/doi/abs/10.1152/ajpcell.1978.235.5.C168 doi:10.1152/ajpcell.1978.235.5.C168]. PMID 727239. S2CID [https://www.semanticscholar.org/paper/Possible-role-of-gap-junctions-in-activation-of-Garfield-Sims/ce78aa441efb2f15ff4749d082197ed4db1b2584 31610495]</ref> It has more recently been discovered that uterine [[macrophage]]s directly physically couples with uterine myocytes through CX43, transferring Ca²⁺, to promote uterine muscle contraction and excitation during labor onset.<ref>Boros-Rausch, A., Shynlova, O., & Lye, S. J. (2021). "A Broad-Spectrum Chemokine Inhibitor Blocks Inflammation-Induced Myometrial Myocyte-Macrophage Crosstalk and Myometrial Contraction". ''Cells''. '''11''' (1): 128. [https://www.mdpi.com/2073-4409/11/1/128 doi: 10.3390/cells11010128] PMID 35011690</ref>