title: Contribution of Ion Channels in Calcium Signaling Regulating Phagocytosis: MaxiK, Cav1.3 and Bestrophin-1.
abstract: Mutations in the BEST1 gene lead to a variety of retinal degenerations including Best's vitelliforme macular degeneration. The BEST1 gene product, bestrophin-1, is expressed in the retinal pigment epithelium (RPE). It is likely that mutant bestrophin-1 impairs functions of the RPE which support photoreceptor function and will thus lead to retinal degeneration. However, the RPE function which is influenced by bestrophin-1 is so far not identified. Previously we showed that bestrophin-1 interacts with L-type Ca²⁺ channels of the CaV1.3 subtype and that the endogenously expressed bestrophin-1 is required for intracellular Ca²⁺ regulation. A hallmark of Best's disease is the fast lipofuscin accumulation occurring already at young ages. Therefore, we addressed the hypothesis that bestrophin-1 might influence phagocytosis of photoreceptor outer segments (POS) by the RPE. Here, siRNA knock-down of bestrophin-1 expression as well as inhibition of L-type Ca²⁺ channel activity modulated the POS phagocytosis in vitro. In vivo CaV1.3 expression appeared to be diurnal regulated with a higher expression rate in the afternoon. Compared to wild-type littermates, Ca V 1.3 (-/-) mice showed a shift in the circadian POS phagocytosis with an increased activity in the afternoon. Thus we suggest that mutant bestrophin-1 leads to an impaired regulation of the POS phagocytosis by the RPE which would explain the fast lipofuscin accumulation in Best patients.
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, Charite University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. olaf.strauss@charite.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Strauß
authors.affiliation: Experimental Ophthalmology, Department of Ophthalmology, Charite University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. Nadine.reichhart@charite.de.
authors.forename: Nadine
authors.initials: N
authors.lastname: Reichhart
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Augustenburger Platz 1, 240 South 40th Street, 19104-6030, Philadelphia, PA, USA. tmspl77@yahoo.es.
authors.forename: Nestor Mas
authors.initials: NM
authors.lastname: Gomez
authors.affiliation: Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University Bronx, 10458, Bronx, NY, USA. mueller_claudi@gmx.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Müller
mesh_terms: D000818:Animals; D000075002:Bestrophins; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009154:Mutation; D010587:Phagocytosis / Q000502:physiology*; D034622:RNA Interference; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D057826:Vitelliform Macular Dystrophy / Q000235:genetics / Q000378:metabolism
chemical_list: C491856:Best1 protein, mouse; D000075002:Bestrophins; C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D005136:Eye Proteins; D007473:Ion Channels; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D002118:Calcium
keywords: BEST1; Best disease; Bestrophin-1; Ca2 + signaling; CaV1.3; MaxiK; Phagocytosis; Retinal pigment epithelium; Transgenic mice; Vitelliform macular dystrophy