Pikachurin

2017-11-27T06:59:15Z

2001:8003:4554:B500:20FE:467E:77A3:1BFA: /* Discovery and nomenclature */

{{Infobox_gene}}
'''Pikachurin''', also known as ''' AGRINL ''' (AGRINL) and '''EGF-like, fibronectin type-III and laminin G-like domain-containing protein''' (EGFLAM), is a protein that in humans is encoded by the ''EGFLAM'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: EGF-like| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=133584| accessdate = }}</ref><ref name="pmid18641643">{{cite journal | vauthors = Sato S, Omori Y, Katoh K, Kondo M, Kanagawa M, Miyata K, Funabiki K, Koyasu T, Kajimura N, Miyoshi T, Sawai H, Kobayashi K, Tani A, Toda T, Usukura J, Tano Y, Fujikado T, Furukawa T | title = Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation | journal = Nature Neuroscience | volume = 11 | issue = 8 | pages = 923–31 | date = August 2008 | pmid = 18641643 | doi = 10.1038/nn.2160 }}</ref><ref name="pmid20078962">{{cite journal | vauthors = Gu XH, Lu Y, Ma D, Liu XS, Guo SW | title = [Model of aberrant DNA methylation patterns and its applications in epithelial ovarian cancer.] | language = Chinese | journal = Zhonghua Fu Chan Ke Za Zhi | volume = 44 | issue = 10 | pages = 754–9 | date = October 2009 | pmid = 20078962 | doi = }}</ref>

Pikachurin is a [[dystroglycan]]-interacting protein which has an essential role in the precise interactions between the [[photoreceptor cell|photoreceptor]] [[ribbon synapse]] and the bipolar [[dendrite]]s.<ref name="pmid18641643"/> The binding with [[dystroglycan]] (DG) depends on several factors ([[glycosylation]] of DG, presence of divalent cations, presence of other proteins).

A non-correct binding between pikachurin and DG is associated with [[muscular dystrophies]] that often involve eye abnormalities.<ref name="Kanagawa_2010">{{cite journal | vauthors = Kanagawa M, Omori Y, Sato S, Kobayashi K, Miyagoe-Suzuki Y, Takeda S, Endo T, Furukawa T, Toda T | title = Post-translational maturation of dystroglycan is necessary for pikachurin binding and ribbon synaptic localization | journal = The Journal of Biological Chemistry | volume = 285 | issue = 41 | pages = 31208–16 | date = October 2010 | pmid = 20682766 | pmc = 2951195 | doi = 10.1074/jbc.M110.116343 }}</ref>

== Discovery and nomenclature ==

Pikachurin is an [[extracellular matrix]]-like [[retina]]l [[protein]] first described in 2008 in Japan by Shigeru Sato et al., and named after [[Pikachu]], a species of the ''[[Pokémon]]'' franchise.<ref name="pmid18641643"/> The name of this "nimble" protein was inspired due to Pikachu's "lightning-fast moves and shocking electric effects".<ref>{{cite news | url = http://inventorspot.com/articles/lightningfast_vision_protein_named_after_pikachu_16170 | title = Lightning-Fast Vision Protein Named After Pikachu | publisher = Inventor Spot | author = Levenstein, Steve | date = 2008-07-24 | accessdate = 2008-07-29 }}</ref>

Pikachurin was initially identified in a [[microarray analysis]] of gene expression profiles of the retinas of wild-type and [[orthodenticle homeobox 2|Otx2]] knockout mice. A [[RT-PCR]] analysis was used to confirm that Otx2 regulates the expression of pikachurin, it was known because there was an absence of expression of pikachurin in the Otx2 mice retina, so it indicates that Otx2 regulates pikachurin. The localization of pikachurin to synaptic cleft in the photoreceptor ribbon synapse was determined using fluorescent antibodies. Tissue targeting of gene disruption of pikachurin was used to determine that this protein is necessary for proper synaptic signal transmission and visual function. α-dystroglycan was shown to interact with pikachurin through [[immunoprecipitation]].<ref name="pmid18641643"/>

== Pikachurin-dystroglycan interaction ==

[[Dystroglycan]] ligand with other proteins is essential. [[Glycosylation]] of [[dystroglycan]] is necessary for its ligand binding activity. Mutations in glycosyltransferase enzymes cause abnormal [[glycosylation]] of [[dystroglycan]]. This hypoglycosylation is associated with less binding with other proteins and causes some congenital muscular dystrophy. Pikachurin is the most recently identified [[dystroglycan]] ligand protein and is localized in the synaptic cleft in the photoreceptor ribbon synapse. The binding between [[dystroglycan]] and pikachurin requires divalent cations. Ca2+ produces strongest binding; Mn2+ produces only faint bindings and no binding with Mg2+ alone. [[Dystroglycan]] has different domains that allow multiple Ca2+ sites to form a stable pikachurin-[[dystroglycan]] connection. This shows that pikachurin can form oligomeric structures; and suggests the possibility of clustering effects can be important in modulating pikachurin-[[dystroglycan]] interactions.
Another thing to be considered is that the presence of NaCl (0.5M) strongly inhibits interaction between DG and other ligand proteins but has a modest inhibitory effect with pikachurin-DG ligand. This shows that there are differences between the binding of pikachurin-DG binding and DG binding with other proteins.
Pikachurin seems to have more domains to bind with DG than other proteins. For example, experiments in ligand competition shows that presence of pikachurin inhibits [[Laminin 111|laminin-111]] binding with DG, but high concentrations of laminin-111 do not inhibit pikachurin binding to DG.<ref name="Kanagawa_2010"/>

== Function ==
[[Image:Pikachurin.jpg|thumb|Comparison between the ribbon synapses in wild-type mice (left) and pikachurin-null mice (right)]]
The protein is colocalized with both [[dystrophin]] and [[dystroglycan]] at the [[ribbon synapse]]s.

Pikachurin, along with [[laminin]], [[perlecan]], [[agrin]], [[neurexin]], binds to α-[[dystroglycan]] in the extracellular space. As such, pikachurin, as well as the other previously-mentioned proteins, is necessary for the proper functioning of dystroglycan. Pikachurin is necessary for the apposition of presynaptic and postsynaptic termini in the ribbon synapse; deletion of pikachurin causes an abnormal [[electroretinogram]], similarly to the deletion of [[nestin (protein)|nestin]].<ref name="pmid19846701">{{cite journal | vauthors = Satz JS, Philp AR, Nguyen H, Kusano H, Lee J, Turk R, Riker MJ, Hernández J, Weiss RM, Anderson MG, Mullins RF, Moore SA, Stone EM, Campbell KP | title = Visual impairment in the absence of dystroglycan | journal = The Journal of Neuroscience | volume = 29 | issue = 42 | pages = 13136–46 | date = October 2009 | pmid = 19846701 | pmc = 2965532 | doi = 10.1523/JNEUROSCI.0474-09.2009 }}</ref>

=== Ribbon synapse relation ===
[[File:Ribbon Synapse.png|thumb|Ribbon synapse showing the position of Pikachurin]]

[[Synapse]] formation is crucial for the mammalian CNS ([[central nervous system]]) to function correctly. Retinal photoreceptors finish at the axon terminal which forms a specialized structure, the ribbon synapse, which specifically connects photoreceptor synaptic terminals with bipolar and horizontal cell terminals in the [[outer plexiform layer]] (OPL) of the retina.<ref name="pmid18641643"/>
It is clear that Pikachurin, an extracellular matrix–like retinal protein, is localized to the synaptic cleft in the photoreceptor ribbon synapse.<ref name="Jakob_2008">{{cite journal | vauthors = Satz JS, Campbell KP | title = Unraveling the ribbon synapse | journal = Nature Neuroscience | volume = 11 | issue = 8 | pages = 857–9 | date = August 2008 | pmid = 18660835 | doi = 10.1038/nn0808-857 }}</ref> It is demonstrated that with a lack of Pikachurin, there is an improper apposition of the [[bipolar cell]] dendritic tips to the photoreceptor [[ribbon synapse]]s, resulting in alterations in synaptic signal transmission and visual function. The function of Pikachurin remains unknown, but it is a fact that pikachurin is critically involved in the normal photoreceptor ribbon synapse formation and also in physiological functions of visual perception.<ref name="Hu_2011">{{cite journal | vauthors = Hu H, Li J, Zhang Z, Yu M | title = Pikachurin interaction with dystroglycan is diminished by defective O-mannosyl glycosylation in congenital muscular dystrophy models and rescued by LARGE overexpression | journal = Neuroscience Letters | volume = 489 | issue = 1 | pages = 10–5 | date = February 2011 | pmid = 21129441 | pmc = 3018538 | doi = 10.1016/j.neulet.2010.11.056 }}</ref>

== Associated pathologies: muscular dystrophies ==

[[Congenital muscular dystrophies]] (CMD) such as muscle-eye-brain disease are caused by defective glycosylation of α-dystroglycan (α-DG) exhibit defective photoreceptor synaptic function. Pikachurin plays an essential role in CMD. Precise interactions between the photoreceptor ribbon synapse and the bipolar dendrites which are realized due to Pikachurin may advance our understanding of the molecular mechanisms underlying the retinal electrophysiological abnormalities observed in muscular dystrophy patients. The muscle-eye-brain dystrophy is caused by mutations in [[POMGnT1]] or [[LARGE]]. These two genes mediated a post-translational modification on O-mannose, which is essential for pikachurin binding to dystroglycan, so people who suffer muscle-eye-disease have an hypoglycosylation of pikachurin-α-dystroglycan interactions.<ref name="Hu_2011"/>

== Therapeutic applications ==

Since pikachurin seems to provide better [[visual acuity]], Sato et al. of the [[Osaka Bioscience Institute]] believe that the protein could be used to develop a treatment for {{SWL|target=retinitis pigmentosa|type=might_be_useful_for_treating}} and other eye disorders.<ref name="pmid18641643"/><ref>{{cite news | url =http://www.yomiuri.co.jp/dy/features/science/20080722TDY02306.htm|title=Researchers: 'Pikachurin' protein linked with kinetic vision|publisher=[[Yomiuri Shimbun]]|date=2008-07-22|accessdate= 2008-07-22 |archiveurl = https://web.archive.org/web/20080727140433/http://www.yomiuri.co.jp/dy/features/science/20080722TDY02306.htm  |archivedate = 2008-07-27}}</ref>

== See also ==
* [[Sonic hedgehog]], another protein named after [[Sonic the Hedgehog (character)|a video game character]].
* [[Zbtb7]], an [[oncogene]] that was originally named "Pokémon".
* [[Aerodactylus]], a genus of pre-historic [[pterosaur]]s named after [[List of generation I Pokémon#Aerodactyl|Aerodactyl]], a pterosaur in the Pokémon franchise.

== References ==
{{reflist|33em}}

== External links ==
* [http://inventorspot.com/articles/lightningfast_vision_protein_named_after_pikachu_16170 Lightning-Fast Vision Protein Named After Pikachu] - July 24, 2008

[[Category:Proteins]]
[[Category:Pokémon]]
[[Category:Genes on human chromosome 5]]

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Pikachurin