Retinoschisin (RS1), the Protein Encoded by the X-linked Retinoschisis Gene, Is Anchored to the Surface of Retinal Photoreceptor and Bipolar Cells through Its Interactions with a Na/K ATPase-SARM1 Complex

Retinoschisin or RS1 is a discoidin domain-containing protein encoded by the gene responsible for X-linked retinoschisis (XLRS), an early onset macular degeneration characterized by a splitting of the retina. Retinoschisin, expressed and secreted from photoreceptors and bipolar cells as a homo-octameric complex, associates with the surface of these cells where it serves to maintain the cellular organization of the retina and the photoreceptor-bipolar synaptic structure. To gain insight into the role of retinoschisin in retinal cell adhesion and the pathogenesis of XLRS, we have investigated membrane components in retinal extracts that interact with retinoschisin. Unlike the discoidin domain-containing blood coagulation proteins Factor V and Factor VIII, retinoschisin did not bind to phospholipids or retinal lipids reconstituted into unilamellar vesicles or immobilized on microtiter plates. Instead, co-immunoprecipitation studies together with mass spectrometric-based proteomics and Western blotting showed that retinoschisin is associated with a complex consisting of Na/K ATPase (α3, β2 isoforms) and the sterile alpha and TIR motif-containing protein SARM1. Double labeling studies for immunofluorescence microscopy confirmed the co-localization of retinoschisin with Na/K ATPase and SARM1 in photoreceptors and bipolar cells of retina tissue. We conclude that retinoschisin binds to Na/K ATPase on photoreceptor and bipolar cells. This interaction may be part of a novel SARM1-mediated cell signaling pathway required for the maintenance of retinal cell organization and photoreceptor-bipolar synaptic structure. Retinoschisin or RS1 is a discoidin domain-containing protein encoded by the gene responsible for X-linked retinoschisis (XLRS), an early onset macular degeneration characterized by a splitting of the retina. Retinoschisin, expressed and secreted from photoreceptors and bipolar cells as a homo-octameric complex, associates with the surface of these cells where it serves to maintain the cellular organization of the retina and the photoreceptor-bipolar synaptic structure. To gain insight into the role of retinoschisin in retinal cell adhesion and the pathogenesis of XLRS, we have investigated membrane components in retinal extracts that interact with retinoschisin. Unlike the discoidin domain-containing blood coagulation proteins Factor V and Factor VIII, retinoschisin did not bind to phospholipids or retinal lipids reconstituted into unilamellar vesicles or immobilized on microtiter plates. Instead, co-immunoprecipitation studies together with mass spectrometric-based proteomics and Western blotting showed that retinoschisin is associated with a complex consisting of Na/K ATPase (α3, β2 isoforms) and the sterile alpha and TIR motif-containing protein SARM1. Double labeling studies for immunofluorescence microscopy confirmed the co-localization of retinoschisin with Na/K ATPase and SARM1 in photoreceptors and bipolar cells of retina tissue. We conclude that retinoschisin binds to Na/K ATPase on photoreceptor and bipolar cells. This interaction may be part of a novel SARM1-mediated cell signaling pathway required for the maintenance of retinal cell organization and photoreceptor-bipolar synaptic structure. Retinoschisin, also known as RS1, 3The abbreviations used are: RS1, retinoschisin; XLRS, X-linked retinoschisis; ER, endoplasmic reticulum; ERGs, electroretinograms; DOPC, dioleoylphosphatidylcholine; DOPE, dioleoylphosphatidylethanolamine; DOPS, dioleoylphosphatidylserine; FVa, activated Factor Va; GST, glutathione S-transferase; PBS, phosphate-buffered saline; TBS, Tris-buffered saline; CHAPS, 3-[(3-cholamidopropyl)dimethylammoniol]-1-propanesulfonate; PB, phosphate buffer. 3The abbreviations used are: RS1, retinoschisin; XLRS, X-linked retinoschisis; ER, endoplasmic reticulum; ERGs, electroretinograms; DOPC, dioleoylphosphatidylcholine; DOPE, dioleoylphosphatidylethanolamine; DOPS, dioleoylphosphatidylserine; FVa, activated Factor Va; GST, glutathione S-transferase; PBS, phosphate-buffered saline; TBS, Tris-buffered saline; CHAPS, 3-[(3-cholamidopropyl)dimethylammoniol]-1-propanesulfonate; PB, phosphate buffer. is a retinal-specific protein encoded by the gene associated with X-linked retinoschisis (XLRS), a leading cause of early onset macular degeneration in males (1Sauer C.G. Gehrig A. Warneke-Wittstock R. Marquardt A. Ewing C.C. Gibson A. Lorenz B. Jurklies B. Weber B.H. Nat. Genet. 1997; 17: 164-170Crossref PubMed Scopus (417) Google Scholar). It is primarily expressed in photoreceptors and to a lesser extent bipolar cells of the adult retina (2Takada Y. Fariss R.N. Tanikawa A. Zeng Y. Carper D. Bush R. Sieving P.A. Invest. Ophthalmol. Vis. Sci. 2004; 45: 3302-3312Crossref PubMed Scopus (85) Google Scholar, 3Molday L.L. Hicks D. Sauer C.G. Weber B.H. Molday R.S. Investig. Ophthalmol. Vis. Sci. 2001; 42: 816-825PubMed Google Scholar, 4Reid S.N. Akhmedov N.B. Piriev N.I. Kozak C.A. Danciger M. Farber D.B. Gene (Amst.). 1999; 227: 257-266Crossref PubMed Scopus (65) Google Scholar). Retinoschisin consists of a 23-amino acid N-terminal signal peptide and a 157-amino acid discoidin domain flanked by a unique 39-amino acid Rs1 domain and a 5-amino acid C-terminal segment (5Wu W.W. Molday R.S. J. Biol. Chem. 2003; 278: 28139-28146Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 6Molday R.S. Exp. Eye Res. 2007; 84: 227-228Crossref PubMed Scopus (41) Google Scholar). The signal peptide directs the nascent polypeptide across the ER membrane before its removal by a signal peptidase in the lumen of the ER. The processed polypeptide folds into its native conformation and further assembles into a disulfide-linked homo-octameric complex prior to secretion from cells (7Wu W.W. Wong J.P. Kast J. Molday R.S. J. Biol. Chem. 2005; 280: 10721-10730Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). The secreted, disulfide-linked octamer associates with the external surface of rod and cone photoreceptor cells of the outer retina and bipolar cells of the inner retina (3Molday L.L. Hicks D. Sauer C.G. Weber B.H. Molday R.S. Investig. Ophthalmol. Vis. Sci. 2001; 42: 816-825PubMed Google Scholar). The function of retinoschisin is not known at the present time. However, the characteristic features of XLRS patients and retinoschisin knock-out mice suggest that this extracellular protein plays a crucial role in maintaining the cellular organization and synaptic structure of the retina. XLRS is characterized by a splitting of the retinal cell layers, a loss in central vision, and a decrease in the b-wave amplitude of the ERG (8George N.D. Yates J.R. Moore A.T. Br. J. Ophthalmol. 1995; 79: 697-702Crossref PubMed Scopus (182) Google Scholar, 9Tantri A. Vrabec T.R. Cu-Unjieng A. Frost A. Annesley Jr., W.H. Donoso L.A. Surv. Ophthalmol. 2004; 49: 214-230Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 10Sikkink S.K. Biswas S. Parry N.R. Stanga P.E. Trump D. J. Med. Genet. 2007; 44: 225-232Crossref PubMed Scopus (136) Google Scholar). To date over 130 disease-causing mutations in the RS1 gene have been identified. In vitro studies have shown that most disease-causing missense mutations in the discoidin domain of retinoschisin cause protein misfolding and retention in ER of cells (5Wu W.W. Molday R.S. J. Biol. Chem. 2003; 278: 28139-28146Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 12Wang T. Waters C.T. Rothman A.M. Jakins T.J. Romisch K. Trump D. Hum. Mol. Genet. 2002; 11: 3097-3105Crossref PubMed Scopus (83) Google Scholar, 13Wang T. Zhou A. Waters C.T. O'Connor E. Read R.J. Trump D. Br. J. Ophthalmol. 2006; 90: 81-86Crossref PubMed Scopus (72) Google Scholar, 14Dyka F.M. Molday R.S. Investig. Ophthalmol. Vis. Sci. 2007; 48: 2491-2497Crossref PubMed Scopus (20) Google Scholar). Mutations in cysteine residues within the Rs1 domain and the C-terminal segment result in normal protein folding and secretion, but defective disulfide-linked octamer formation (5Wu W.W. Molday R.S. J. Biol. Chem. 2003; 278: 28139-28146Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 7Wu W.W. Wong J.P. Kast J. Molday R.S. J. Biol. Chem. 2005; 280: 10721-10730Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Retinoschisin knock-out mice exhibit many features found in XLRS pathology (15Weber B.H. Schrewe H. Molday L.L. Gehrig A. White K.L. Seeliger M.W. Jaissle G.B. Friedburg C. Tamm E. Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6222-6227Crossref PubMed Scopus (180) Google Scholar). These include a marked disorganization of the retinal cell layers with gaps between bipolar cells of the inner of the photoreceptor-bipolar synaptic structure of the outer in the b-wave amplitude of and ERGs, and degeneration of rod and cone photoreceptor cells. these studies suggest that loss in retinoschisin function the of the retina and normal signal across the photoreceptor-bipolar The discoidin also known as the is the of retinoschisin (1Sauer C.G. Gehrig A. Warneke-Wittstock R. Marquardt A. Ewing C.C. Gibson A. Lorenz B. Jurklies B. Weber B.H. Nat. Genet. 1997; 17: 164-170Crossref PubMed Scopus (417) Google Scholar). in discoidin proteins of the S. E. J. Mol. Biol. PubMed Scopus Google Scholar). have been found in a of extracellular and cell surface membrane proteins that function in cell and signaling S. K. R. Sci. PubMed Scopus Google Scholar). These include blood coagulation V and VIII, discoidin domain and S. K. R. Sci. PubMed Scopus Google Scholar, K. Sci. 2002; PubMed Scopus (65) Google Scholar). The structure of the discoidin domain of Factor V and Factor and the discoidin domain of have been by S. R. W.H. 1999; PubMed Scopus Google Scholar, K. K. 1999; PubMed Scopus Google Scholar, C.C. A. D. K. 2003; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). In it is of a structure in a a of the the discoidin domain is the formation of a between cysteine residues at the and of the discoidin the or from the structure and a or that serves as the K. Sci. 2002; PubMed Scopus (65) Google Scholar, C.C. A. D. K. 2003; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). The of the of Factor V and Factor have been used to a for the discoidin domain of retinoschisin (5Wu W.W. Molday R.S. J. Biol. Chem. 2003; 278: 28139-28146Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 2003; PubMed Scopus Google Scholar). Factor V and VIII, it a structure with a have been to bind a of cellular coagulation proteins Factor V and Factor known to bind to cell surface phospholipids and in discoidin domain and interact with and binds and proteins K. Sci. 2002; PubMed Scopus (65) Google Scholar, C.C. A. D. K. 2003; 11: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Mol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). and of D. on the have been to have a for and in S. E. J. Mol. Biol. PubMed Scopus Google Scholar). retinoschisin associates with retinal cell surface (3Molday L.L. Hicks D. Sauer C.G. Weber B.H. Molday R.S. Investig. Ophthalmol. Vis. Sci. 2001; 42: 816-825PubMed Google Scholar, S.N. C. Farber D.B. J. 2003; PubMed Google the of the components that retinoschisin to these is not known at the present time. and of the retinoschisin discoidin have to the that blood coagulation V and VIII, may bind to membrane phospholipids 2003; PubMed Scopus Google Scholar). In this we have used mass and to components in retinal extracts that interact with retinoschisin. studies that retinoschisin not bind to membrane but a complex with Na/K ATPase and SARM1. This interaction retinoschisin in a novel signal pathway in photoreceptor-bipolar synaptic structure and function and retinal cell and from activated Factor and an from The SARM1 from ATPase from and an ATPase β2 from The RS1 and have been (3Molday L.L. Hicks D. Sauer C.G. Weber B.H. Molday R.S. Investig. Ophthalmol. Vis. Sci. 2001; 42: 816-825PubMed Google Scholar, B.H. Schrewe H. Molday L.L. Gehrig A. White K.L. Seeliger M.W. Jaissle G.B. Friedburg C. Tamm E. Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6222-6227Crossref PubMed Scopus (180) Google Scholar). from the Eye of cells in the the secreted retinoschisin at for to cell and with at The in at the of the cell The and at for to retinoschisin further by on a The retinoschisin protein with of at in the retinoschisin with and to the retinoschisin and from retina as (7Wu W.W. Wong J.P. Kast J. Molday R.S. J. Biol. Chem. 2005; 280: 10721-10730Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). of from retinal cell the of and J. PubMed Scopus Google Scholar). retinal in a consisting of part and a of and the in a and at for to a The the lipids and to a unilamellar vesicles by the of M. PubMed Scopus Google Scholar). phospholipids of to DOPS, of to or of in a of and to a a of The phospholipids or retinal lipids with and J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The vesicles to in to and The vesicles a membrane a to unilamellar the vesicles and of Factor and Retinoschisin to of and retinoschisin to vesicles in for at a of of phospholipids with of or retinoschisin in a of at for The at for in a The protein and the the vesicles by with to The in of and the and by and Western studies at of and Retinoschisin to of or retinoschisin to phospholipids immobilized microtiter by a of the of D. M. W.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). or in at a of and to of a microtiter The lipids to at The with of for at and with phosphate and studies by of or retinoschisin in and to at the with and with of or RS1 or in for at The with and with of to at a for at The and with of acid in The at in a microtiter in Western and in and and on or Western proteins a The in in for and for with the in in at the The in and for with a or to or for on a by the of or in of and for on cells a and a The on of in and in an for at The retinal on of the and by the of retinal from or mice (15Weber B.H. Schrewe H. Molday L.L. Gehrig A. White K.L. Seeliger M.W. Jaissle G.B. Friedburg C. Tamm E. Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6222-6227Crossref PubMed Scopus (180) Google in and The by a and the retinal by on a as of Retinoschisin from and retinal in of in and retinal in of in and The at for and in for at to of the Na/K ATPase and SARM1 proteins from retinal these The to of with the RS1 retinoschisin an as a as (5Wu W.W. Molday R.S. J. Biol. Chem. 2003; 278: 28139-28146Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). The for at with in an The in by to protein with in or with of the peptide in by a with in The protein by of proteins by the from a with a The with to acid and in a of and with the and with by with and from The the with at in and for on The and the with and The for at The in a and the with and with The in a and in of mass to The and with of before acid in a with and on a mass and a used for of as and reconstituted in with a and from used for peptide and in and in at with a to over to at and for before to B. the from mice in phosphate for The with phosphate in and The and in and in for and at with the retinoschisin and to Na/K ATPase in and ATPase The with and for with to or in and a with an of and to discoidin domain of blood coagulation Factor V is known to bind phospholipids and in S. R. W.H. 1999; PubMed Scopus Google Scholar, H. T. PubMed Scopus Google Scholar). This interaction the complex to on the surface of as a in the blood coagulation Retinoschisin associates with retinal and in the extracellular of photoreceptor and bipolar cells (3Molday L.L. Hicks D. Sauer C.G. Weber B.H. Molday R.S. Investig. Ophthalmol. Vis. Sci. 2001; 42: 816-825PubMed Google Scholar, S.N. C. Farber D.B. J. 2003; PubMed Google Scholar). and of the retinoschisin discoidin domain to the that retinoschisin Factor V may bind to the the interaction of residues within the of the discoidin domain 2003; PubMed Scopus Google Scholar). To retinoschisin binds to membrane microtiter immobilized or with retinoschisin or of Factor as a and protein by that binds to DOPS, but not in with its known D. M. W.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, H. T. PubMed Scopus Google Scholar). In of retinoschisin to immobilized or of Retinoschisin and to is that retinoschisin binds to phospholipids in a This investigated by the of and retinoschisin to unilamellar vesicles consisting of or at a of and at a of with retinoschisin or as a in the of The vesicles from the protein by for by Western that a of to but not vesicles as In retinoschisin did not bind to or vesicles to vesicles consisting of an retinoschisin did not not part of this the interaction of retinoschisin and with unilamellar vesicles of retinal membrane lipids showed to retinal of retinoschisin and we retinoschisin from retina with retinoschisin secreted from cells for to shown in retinoschisin from to bind to of with the studies that retinoschisin not bind to membrane we the interaction of retinoschisin with retinal proteins by retinal cell to an consisting of the to protein by the proteins with a of proteins from retinal from the of to proteins with of and retina used in of retinal in co-immunoprecipitation The proteins from the from by and the protein as the Na/K ATPase and the protein as a sterile alpha and TIR motif-containing proteins present in the mass of as the Na/K ATPase retinoschisin and Retinoschisin and the in the of The to from of RS1 from the with In to these a in and used to the also by mass The retinal membrane proteins present in the from the in of retinal proteins that with retinoschisin on an RS1 to the on the in of ATPase alpha TIR motif-containing protein ATPase to the on the in in a Western of from the Retinoschisin blotting used to the mass of proteins that with retinoschisin on a RS1 Western of the retinal membrane to the and the from the with The Na/K ATPase Na/K ATPase and SARM1 in the with the retinoschisin and a studies to the of the RS1 retinal to an the or an as a the proteins with the peptide and with a of the and and that to the RS1 with The protein with In retinoschisin and Na/K ATPase β2 not in the from the and labeling of the Na/K ATPase SARM1 to the RS1 and not in the from the not Retinoschisin for the of Na/K ATPase on a RS1 ATPase is a membrane protein in the retina and in photoreceptor cells E. J. 1999; PubMed Google Scholar). it is that of Na/K ATPase with retinoschisin be to interaction with the RS1 This investigated by co-immunoprecipitation studies of retinal from and mice (15Weber B.H. Schrewe H. Molday L.L. Gehrig A. White K.L. Seeliger M.W. Jaissle G.B. Friedburg C. Tamm E. Molday R.S. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6222-6227Crossref PubMed Scopus (180) Google Scholar). that a of Na/K ATPase with retinoschisin retinal of mice to a RS1 In Na/K ATPase not in the retinal of mice to the for SARM1. These studies that Na/K ATPase and SARM1 not bind to the RS1 but with retinoschisin as a result of of Na/K ATPase with Retinoschisin and SARM1 in microscopy used to the of Na/K ATPase and SARM1 in retinal of adult of retinoschisin and Na/K ATPase in photoreceptor inner outer and inner of the retina and within the outer and inner confirmed a of of the Na/K ATPase and retinoschisin in the retinal layers also with a to SARM1. The labeling to that of Na/K ATPase and retinoschisin with labeling in the inner outer and layers of the outer retina and inner and inner layers of the inner retina Double labeling studies that SARM1 with Na/K ATPase in these layers In the SARM1 the retinal and cells with the that SARM1 is in most cells. In labeling the Na/K or SARM1 in the labeling not a the SARM1 for this a of protein in Western of retinal extracts it is that of the immunofluorescence labeling with the SARM1 is in We in the of SARM1 to further the of SARM1 in retina tissue. To gain insight into the and cellular the role of retinoschisin in the normal retina structure and function and the pathogenesis of XLRS, we the interaction of retinoschisin with retinal membrane lipids and studies that retinoschisin is not to photoreceptor and bipolar surface but is to these cells its interaction with a protein complex consisting of the Na/K ATPase and SARM1. we the that retinoschisin may interact with membrane lipids its discoidin domain to the of blood coagulation proteins Factor V and to on blood that retinoschisin not bind to or retinal lipids immobilized on microtiter or in with in these as D. M. W.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, H. T. PubMed Scopus Google Scholar). C. Y. Zeng Y. Bush Sieving P.A. Investig. Ophthalmol. Vis. Sci. 2007; 48: PubMed Scopus Google a that the discoidin domain of retinoschisin a for phospholipids for this interaction on the that proteins and retinoschisin discoidin to of of this on the of this the used in these to as by the of these the that be used to the with these This not in proteins the retinoschisin discoidin domain used in these of the native retinoschisin homo-octameric complex as used in the It is that the discoidin domain of retinoschisin folds in the of and to its native structure. the of the proteins not This is a of the discoidin domain used in this to bind the phospholipids as the discoidin domain C. Y. Zeng Y. Bush Sieving P.A. Investig. Ophthalmol. Vis. Sci. 2007; 48: PubMed Scopus Google the that these proteins have been to be expressed in cells T. Zhou A. Waters C.T. O'Connor E. Read R.J. Trump D. Br. J. Ophthalmol. 2006; 90: 81-86Crossref PubMed Scopus (72) Google Scholar). it is that the discoidin not and be used as to the of native and retinoschisin. that native retinoschisin not bind to immobilized lipids or lipids in a together with the in domain proteins and retinoschisin to cell its interaction with membrane the studies for the of retinoschisin to photoreceptor and bipolar cell a retinal membrane in to an the Na/K ATPase and with retinoschisin as by mass and confirmed by Western the of interaction between these proteins and retinoschisin. Na/K ATPase in the from an in the RS1 with an retinal membrane extracts from mice to the RS1 Na/K ATPase SARM1 in the that retinoschisin is required for of these a of Na/K ATPase with retinoschisin the RS1 with the peptide Na/K ATPase is the for retinoschisin to the surface of photoreceptor and bipolar cells. Na/K an membrane protein found on the membrane of is of and as a J. Google Scholar). is found in many The and is the responsible for the of and across The with a segment plays a role in the of the complex, to cell and of the of the have with and In the present the and β2 in the from a retinoschisin as by mass and confirmed by Western These have been shown to be expressed in photoreceptor and bipolar cells and in the inner outer and outer layers of the outer retina and the inner the bipolar cells of the inner retina in adult and E. J. 1999; PubMed Google Scholar). In the present we have shown that retinoschisin and Na/K ATPase exhibit a of labeling with in the inner outer and inner layers and in the outer and inner of Na/K ATPase and retinoschisin further confirmed the co-localization of these proteins in the retina. SARM1 with Na/K ATPase over of the with its in this Retinoschisin most binds to the of Na/K This a extracellular domain with to and as a result on with an mass of of the protein mass of S. H. S. R. M. M. J. Biol. PubMed Scopus Google Scholar). Retinoschisin, discoidin domain an for PubMed Scopus Google Scholar). S. it is that the of the may to retinoschisin this to be The of Na/K ATPase extracellular the and is to a for retinoschisin. the also known as on been in cell adhesion S. H. S. R. M. M. J. Biol. PubMed Scopus Google Scholar, H. E. M. J. Biol. PubMed Scopus Google Scholar). In to Na/K also known as sterile alpha and TIR motif-containing protein present in the that with retinoschisin from the SARM1 is a acid protein sterile alpha flanked by and a domain M. B. K. K. 2001; PubMed Scopus Google Scholar). These have been found in a of membrane and proteins and have been in SARM1 as by membrane or and is to interact with retinoschisin. The function of SARM1 is not but a that it with and an protein that as part of the signaling pathway associated with M. R. M. J. Nat. 2006; PubMed Scopus Google Scholar, L.A. Nat. 2007; PubMed Scopus Google Scholar). The interaction of SARM1 with the and TIR of SARM1. studies suggest that SARM1 may function as a protein in a novel retinal cell signaling SARM1 most binds to a within the of the of Na/K its and TIR it bind to protein that with Na/K a protein not been in Retinoschisin is a homo-octameric complex in together between cysteine residues and (7Wu W.W. Wong J.P. Kast J. Molday R.S. J. Biol. Chem. 2005; 280: 10721-10730Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). of of these cysteine residues with or in normal retinoschisin and secretion, but defective (5Wu W.W. Molday R.S. J. Biol. Chem. 2003; 278: 28139-28146Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 7Wu W.W. Wong J.P. Kast J. Molday R.S. J. Biol. Chem. 2005; 280: 10721-10730Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). The of octamer formation is by the that and mutations in retinoschisin known to octamer formation (5Wu W.W. Molday R.S. J. Biol. Chem. 2003; 278: 28139-28146Abstract Full Text Full Text PDF PubMed Scopus (105) Google associated with XLRS R. Hum. Mol. Genet. PubMed Scopus Google Scholar, R. S. Sieving P.A. Hum. 1999; PubMed Scopus Google Scholar, Sieving P.A. Ophthalmol. 2001; Google Scholar). role the structure of retinoschisin on we a in retinoschisin binds to an extracellular on the Na/K ATPase its retinoschisin the of the Na/K ATPase in the a protein SARM1 to bind Na/K ATPase on the of the SARM1 may interact with proteins proteins as part of a cell signaling that is crucial for maintaining normal photoreceptor-bipolar synaptic structure and function and between the extracellular and photoreceptor and bipolar cell The of this is that retinoschisin not interact with components of the extracellular but photoreceptor and bipolar cell function and organization signaling in cell structure. In extracellular proteins interact with the complex the extracellular to photoreceptors and bipolar cells and the cellular and synaptic organization of the retina. In a J. Hicks D. Mol. Vis. 2006; Google that β2 with retinoschisin on an However, β2 showed with retinoschisin in retina by immunofluorescence we have not β2 in co-immunoprecipitation studies and as further studies to β2 or extracellular proteins with ATPase In studies that retinoschisin is to the surface of photoreceptor and bipolar cells its interaction with a complex the Na/K ATPase and SARM1. This complex may be part of a novel signaling pathway for the structure and function of the photoreceptor-bipolar and normal interaction of these cells with the extracellular mutations in retinoschisin in a protein this signaling pathway leading to the of the retinal cell organization and loss in photoreceptor-bipolar synaptic structure and signal as is in patients with XLRS and mice in retinoschisin. in to further the for the ATPase and components of the signal pathway to SARM1. We for with Wong for with the of Weber for the and for

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