Pikachurin

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 is_associated_with::gene.

Pikachurin is a is_associated_with::dystroglycan-interacting protein which has an essential role in the precise interactions between the photoreceptor is_associated_with::ribbon synapse and the bipolar is_associated_with::dendrites. The binding with is_associated_with::dystroglycan (DG) depends on several factors (is_associated_with::glycosylation of DG, presence of divalent cations, presence of other proteins).

A non-correct binding between pikachurin and DG is associated with is_associated_with::muscular dystrophies that often involve eye abnormalities.

Discovery and nomenclature
Pikachurin is an is_associated_with::extracellular matrix-like is_associated_with::retinal is_associated_with::protein first described in 2008 in Japan by Shigeru Sato et al., and named after is_associated_with::Pikachu, a character of the is_associated_with::Pokémon franchise. The name of this "nimble" protein was inspired due to Pikachu's "lightning-fast moves and shocking electric effects".

Pikachurin was initially identified in a is_associated_with::microarray analysis of gene expression profiles of the retinas of wild-type and Otx2 knockout mice. A is_associated_with::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 is_associated_with::immunoprecipitation.

Pikachurin-dystroglycan interaction
is_associated_with::Dystroglycan ligand with other proteins is essential. is_associated_with::Glycosylation of is_associated_with::dystroglycan is necessary for its ligand binding activity. Mutations in glycosyltransferase enzymes cause abnormal is_associated_with::glycosylation of is_associated_with::dystroglycan. This hypoglycosylation is associated with less binding with other proteins and causes some congenital muscular dystrophy. Pikachurin is the most recently identified is_associated_with::dystroglycan ligand protein and is localized in the synaptic cleft in the photoreceptor ribbon synapse. The binding between is_associated_with::dystroglycan and pikachurin requires divalent cations. Ca2+ produces strongest binding; Mn2+ produces only faint bindings and no binding with Mg2+ alone. is_associated_with::Dystroglycan has different domains that allow multiple Ca2+ sites to form a stable pikachurin-is_associated_with::dystroglycan connection. This shows that pikachurin can form oligomeric structures; and suggests the possibility of clustering effects can be important in modulating pikachurin-is_associated_with::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 binding with DG, but high concentrations of laminin-111 do not inhibit pikachurin binding to DG.

Function
The protein is colocalized with both is_associated_with::dystrophin and is_associated_with::dystroglycan at the is_associated_with::ribbon synapses.

Pikachurin, along with is_associated_with::laminin, is_associated_with::perlecan, is_associated_with::agrin, is_associated_with::neurexin, binds to α-is_associated_with::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 is_associated_with::electroretinogram, similarly to the deletion of nestin.

Ribbon synapse relation


is_associated_with::Synapse formation is crucial for the mammalian CNS (is_associated_with::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 is_associated_with::outer plexiform layer (OPL) of the retina. It is clear that Pikachurin, an extracellular matrix–like retinal protein, is localized to the synaptic cleft in the photoreceptor ribbon synapse. It is demonstrated that with a lack of Pikachurin, there is an improper apposition of the is_associated_with::bipolar cell dendritic tips to the photoreceptor is_associated_with::ribbon synapses, 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.

Associated pathologies: muscular dystrophies
is_associated_with::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 is_associated_with::POMGnT1 or is_associated_with::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.

Therapeutic applications
Since pikachurin seems to provide better is_associated_with::visual acuity, Sato et al. of the is_associated_with::Osaka Bioscience Institute believe that the protein could be used to develop a treatment for might_be_useful_for_treating::retinitis pigmentosa and other eye disorders.