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: Olaf Strauß, Nadine Reichhart, Nestor Mas Gomez, Claudia Müller
• Journal: Advances in experimental medicine and biology (Adv Exp Med Biol) Vol. 854 Pg. 739-44 ( 2016) ISSN: 0065-2598 [Print] United States
• PMID: 26427483 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Best1 protein, mouse
• Bestrophins
• Cacna1d protein, mouse
• Calcium Channels, L-Type
• Eye Proteins
• Ion Channels
• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
• Calcium

Topics

• Animals
• Bestrophins
• Calcium (metabolism)
• Calcium Channels, L-Type (genetics, metabolism)
• Calcium Signaling (physiology)
• Eye Proteins (genetics, metabolism)
• Humans
• Ion Channels (genetics, metabolism)
• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits (genetics, metabolism)
• Mice, Knockout
• Mutation
• Phagocytosis (physiology)
• RNA Interference
• Retinal Photoreceptor Cell Outer Segment (metabolism)
• Retinal Pigment Epithelium (metabolism)
• Vitelliform Macular Dystrophy (genetics, metabolism)