Zusammenfassung
Best's vitelliforme macular degeneration is an inherited retinal degeneration associated with a reduction of the light-peak in the patient's electro-oculogram. Bestrophin-1, the product of the disease-promoting/forming gene can function as regulator of voltage-dependent L-type Ca2+ channels in the retinal pigment epithelium (RPE). Since mice deficient for either beta 4-subunits or Ca(v)1.3 ...
Zusammenfassung
Best's vitelliforme macular degeneration is an inherited retinal degeneration associated with a reduction of the light-peak in the patient's electro-oculogram. Bestrophin-1, the product of the disease-promoting/forming gene can function as regulator of voltage-dependent L-type Ca2+ channels in the retinal pigment epithelium (RPE). Since mice deficient for either beta 4-subunits or Ca(v)1.3 subunits show reduced light-peaks, the regulatory function of bestrophin-1 on heterologously expressed Ca2+ channels composed of the pore-forming Cav1.3 and the auxiliary beta 4-subunit was analyzed. Precipitation of beta 4-subunits led to co-precipitation with bestrophin-1 and subsequent analysis of subcellular localization showed co-localization of bestrophin-1, Cav1.3 and beta 4-subunit in the cell membrane. Cav1.3 currents in the presence of beta 4-subunits and bestrophin-1 showed accelerated time-dependent activation and decreased current density compared to currents measured in the absence of bestrophin-1. In the presence of the beta-subunit, which is not expressed in the RPE bestrophin-1 did not modulate Ca(v)1.3 activity. Deletion of a cluster of proline-rich motifs in the C-terminus of bestrophin-1 reduced its co-immuno precipitation with the beta 4-subunit and strongly reduced the Ca(v)1.3 activity. Cells co-expressing bestrophin-1 lacking the proline-rich motifs and Ca(v)1.3 subunits showed less efficient trafficking of bestrophin-1 into the cell membrane. In summary, we conclude that bestrophin-1 modulates L-type channels of the RPE via proline-rich motif-dependent interaction with beta 4-subunits. A disturbed interaction reduces the currents of the Ca(v)1.3 subunits. This mechanism could open new ways to understand changes in the patient's electro-oculogram and functional alterations of the RPE leading to retinal degeneration. (C) 2010 Elsevier Ltd. All rights reserved.
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