The Light Peak of the Electroretinogram Is Dependent on Voltage-gated Calcium Channels and Antagonized by Bestrophin (Best-1)

Journal of General Physiology - Tập 127 Số 5 - Trang 577-589 - 2006
Lihua Y. Marmorstein1, Jiang Wu2, P. J. McLaughlin1, John Yocom1, Michael Karl3, Rudgar Neussert3, Soenke Wimmers3, J. Brett Stanton1, Ronald G. Gregg4, Olaf Strauß3, Neal S. Peachey2,5, Alan D. Marmorstein1,6
11Department of Ophthalmology and Vision Science
23Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
34Experimentelle Ophthalmologie Universitaetsklinkum Hamburg-Eppendorf, Hamburg, Germany
45Biochemistry and Molecular Biology, Ophthalmology and Visual Science, University of Louisville, KY 40202
56Research Service, Cleveland VA Medical Center, Cleveland, OH 44106
62Optical Sciences Center, University of Arizona, Tucson, AZ 85711

Tóm tắt

Mutations in VMD2, encoding bestrophin (best-1), cause Best vitelliform macular dystrophy (BMD), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC). BMD is distinguished from AVMD by a diminished electrooculogram light peak (LP) in the absence of changes in the flash electroretinogram. Although the LP is thought to be generated by best-1, we find enhanced LP luminance responsiveness with normal amplitude in Vmd2−/− mice and no differences in cellular Cl− currents in comparison to Vmd2+/+ littermates. The putative Ca2+ sensitivity of best-1, and our recent observation that best-1 alters the kinetics of voltage-dependent Ca2+ channels (VDCC), led us to examine the role of VDCCs in the LP. Nimodipine diminished the LP, leading us to survey VDCC β-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the β4 subunit of VDCCs, exhibited a significant shift in LP luminance response, establishing a role for Ca2+ in LP generation. When stimulated with ATP, which increases [Ca++]I, retinal pigment epithelial cells derived from Vmd2−/− mice exhibited a fivefold greater response than Vmd2+/+ littermates, indicating that best-1 can suppress the rise in [Ca2+]I associated with the LP. We conclude that VDCCs regulated by a β4 subunit are required to generate the LP and that best-1 antagonizes the LP luminance response potentially via its ability to modulate VDCC function. Furthermore, we suggest that the loss of vision associated with BMD is not caused by the same pathologic process as the diminished LP, but rather is caused by as yet unidentified effects of best-1 on other cellular processes.

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Journal of General Physiology

Tập 127 Số 5

577-589

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