Editing Gap junction (section)

===The bystander effect and disease===

====Cell death====
The ''bystander effect'' has its connotations of the innocent bystander being killed. When cells are dying or compromised due to disease or injury, messages are transmitted to neighboring cells by gap junctions. This can cause otherwise healthy bystander cells to also die.<ref>{{cite journal | pmid = 8186287 | doi=10.1089/hum.1993.4.6-725 | volume=4 | issue=6 | title=In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy |date=December 1993 | journal=Hum. Gene Ther. | pages=725–31 | last1 = Li Bi | first1 = Wan | last2 = Parysek | first2 = Linda M. | last3 = Warnick | first3 = Ronald | last4 = Stambrook | first4 = Peter J.}}</ref> 

The [[Bystander effect (radiobiology)|bystander effect]] was later researched with regard to cells damaged by radiation or mechanical injury and in turn wound healing.<ref>{{cite journal | pmid = 12194273 | volume=99 | issue=1–4 | title=Bystander effects: intercellular transmission of radiation damage signals | year=2002 | journal=Radiat Prot Dosimetry | pages=159–62 | doi = 10.1093/oxfordjournals.rpd.a006751 | last1 = Little | first1 = JB | last2 = Azzam | first2 = EI | last3 = De Toledo | first3 = SM | last4 = Nagasawa | first4 = H}}</ref><ref>{{cite journal | pmid = 12194291 | volume=99 | issue=1–4 | title=Genotoxic damage in non-irradiated cells: contribution from the bystander effect | year=2002 | journal=Radiat Prot Dosimetry | pages=227–32 | doi = 10.1093/oxfordjournals.rpd.a006769 | last1 = Zhou | first1 = H | last2 = Randers-Pehrson | first2 = G | last3 = Suzuki | first3 = M | last4 = Waldren | first4 = CA | last5 = Hei | first5 = TK}}</ref><ref>{{cite journal | pmid = 12556327 | volume=79 | issue=1 | title=Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review |date=January 2003 | journal=Int. J. Radiat. Biol. | pages=15–25 | last1 = Lorimore | first1 = SA | last2 = Wright | first2 = EG | doi=10.1080/0955300021000045664| s2cid=44821116 }}</ref><ref>{{cite journal | pmid = 14617290 | volume=11 | issue=6 | title=Role for gap junctional intercellular communications in wound repair | year=2003 | journal=Wound Repair Regen | pages=481–9 | doi = 10.1046/j.1524-475X.2003.11616.x | last1 = Ehrlich | first1 = HP | last2 = Diez | first2 = T| s2cid=25113646 }}</ref><ref>{{cite journal | pmid = 15927148 | doi=10.1016/j.bjps.2004.12.022 | volume=58 | issue=5 | title=Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury |date=July 2005 | journal=Br J Plast Surg | pages=658–67 | last1 = Coutinho | first1 = P. | last2 = Qiu | first2 = C. | last3 = Frank | first3 = S. | last4 = Wang | first4 = C.M. | last5 = Brown | first5 = T. | last6 = Green | first6 = C.R. | last7 = Becker | first7 = D.L.| doi-access = free }}</ref> Disease seems to have an effect on the ability of gap junctions to fulfill their roles in wound healing.<ref>{{cite journal | pmid = 17717278 | doi=10.2337/db07-0613 | volume=56 | issue=11 | title=Abnormal connexin expression underlies delayed wound healing in diabetic skin |date=November 2007 | journal=Diabetes | pages=2809–17 | last1 = Wang | first1 = C. M. | last2 = Lincoln | first2 = J. | last3 = Cook | first3 = J. E. | last4 = Becker | first4 = D. L.| doi-access = free}}</ref><ref>{{cite journal | pmid = 9550065 | volume=9 | issue=1 | title=Considerations for the aesthetic restoration of endodontically treated anterior teeth following intracoronal bleaching | year=1997 | journal=Pract Periodontics Aesthet Dent | pages=117–28 | last1 = Rivera | first1 = EM | last2 = Vargas | first2 = M | last3 = Ricks-Williamson | first3 = L}}</ref> The oral administration of gap junction blockers to reduce the symptoms of disease in remote parts of the body is slowly becoming a reality.<ref>{{cite journal |last1=Mugisho |first1=Odunayo O. |last2=Aryal |first2=Jyoti |last3=Shorne |first3=Avik |last4=Lyon |first4=Heather |last5=Acosta |first5=Monica L. |last6=Green |first6=Colin R. |last7=Rupenthal |first7=Ilva D. |title=Orally Delivered Connexin43 Hemichannel Blocker, Tonabersat, Inhibits Vascular Breakdown and Inflammasome Activation in a Mouse Model of Diabetic Retinopathy |journal=International Journal of Molecular Sciences |date=15 February 2023 |volume=24 |issue=4 |pages=3876 |doi=10.3390/ijms24043876|pmid=36835288 |pmc=9961562 |doi-access=free }}</ref>

====Tissue restructuring====
While there has been a tendency to focus on the bystander effect in disease due to the possibility of therapeutic avenues, there is evidence that there is a more central role in normal development of tissues. Death of some cells and their surrounding matrix may be required for a tissue to reach its final configuration; gap junctions appear essential to this process.<ref>{{cite journal | pmid = 12878681 | pmc=6740641 | volume=23 | issue=16 | title=Gap junctions mediate bystander cell death in developing retina |date=July 2003 | journal=J. Neurosci. | pages=6413–22 | last1 = Cusato | first1 = K | last2 = Bosco | first2 = A | last3 = Rozental | first3 = R | last4 = Guimarães | first4 = CA | last5 = Reese | first5 = BE | last6 = Linden | first6 = R | last7 = Spray | first7 = DC| doi=10.1523/JNEUROSCI.23-16-06413.2003 }}</ref><ref>{{cite journal | pmid = 15225205 | doi=10.1111/j.1067-1927.2004.012310.x | volume=12 | issue=3 | title=Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication | year=2004 | journal=Wound Repair Regen | pages=269–75 | last1 = Moyer | first1 = Kurtis E. | last2 = Saggers | first2 = Gregory C. | last3 = Ehrlich | first3 = H. Paul| s2cid=24363587 }}</ref> There are also more complex studies that try to combine our understanding of the simultaneous roles of gap junctions in both wound healing and tissue development.<ref>{{cite journal | pmid = 16628254 | doi=10.1172/JCI27186 | pmc=1440704 | volume=116 | issue=5 | title=Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response |date=May 2006 | journal=J. Clin. Invest. | pages=1243–53 | last1 = Djalilian | first1 = A. R. | last2 = McGaughey | first2 = D | last3 = Patel | first3 = S | last4 = Seo | first4 = EY | last5 = Yang | first5 = C | last6 = Cheng | first6 = J | last7 = Tomic | first7 = M | last8 = Sinha | first8 = S | last9 = Ishida-Yamamoto | first9 = A| last10=Segre | first10=J. A. | display-authors=8 }}</ref><ref>{{cite journal | pmid = 19966054 | doi=10.1152/ajpheart.00806.2009 | pmc=2822575 | volume=298 | issue=2 | title=Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-beta signaling |date=February 2010 | journal=Am. J. Physiol. Heart Circ. Physiol. | pages=H477–87 | last1 = Zhang | first1 = Y. | last2 = Wang | first2 = H. | last3 = Kovacs | first3 = A. | last4 = Kanter | first4 = E. M. | last5 = Yamada | first5 = K. A.}}</ref><ref>{{cite journal | vauthors = Ey B, Eyking A, Gerken G, Podolsky DK, Cario E | title = TLR2 mediates gap junctional intercellular communication through connexin-43 in intestinal epithelial barrier injury | journal = J. Biol. Chem. | volume = 284 | issue = 33 | pages = 22332–43 | date = August 2009 | pmid = 19528242 | doi = 10.1074/jbc.M901619200 | pmc=2755956| doi-access = free }}</ref>

====Disease====
Mutations in connexins have been associated with many diseases in humans, including [[deafness]],<ref>{{cite journal |last1=Xu |first1=Ji |last2=Nicholson |first2=Bruce J. |title=The role of connexins in ear and skin physiology — Functional insights from disease-associated mutations |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |date=January 2013 |volume=1828 |issue=1 |pages=167–178 |doi=10.1016/j.bbamem.2012.06.024|pmid=22796187 |pmc=3521577 }}</ref> heart [[atrial fibrillation]] (standstill) and [[cataract]]s. The study of these mutations has helped clarify some of the functions of connexins.<ref>{{cite journal |last1=Srinivas |first1=Miduturu |last2=Verselis |first2=Vytas K. |last3=White |first3=Thomas W. |title=Human diseases associated with connexin mutations |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |date=1 January 2018 |volume=1860 |issue=1 |pages=192–201 |doi=10.1016/j.bbamem.2017.04.024|pmid=28457858 |pmc=5659969 }}</ref><ref>{{Cite journal|pmid=10099690 |year=1999 |first1=Thomas W. |last1=White |first2=David L. |last2=Paul |title=Genetic diseases and gene knockouts reveal diverse connexin functions |volume=61 |pages=283–310 |doi=10.1146/annurev.physiol.61.1.283 |journal=Annual Review of Physiology |issue=1}}</ref>

Hemichannels are thought to play a general role in the progression and severity of many diseases; this is in part due to hemichannels being an open door to the outside of each cell.<ref name="hemichannel"/>