The Journal of General Physiology
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Published online Apr 24 2006. doi:10.1085/jgp.200509473
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 127, Number 5, 577-589
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ARTICLE

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



Lihua Y. Marmorstein1, Jiang Wu3, Precious McLaughlin1, John Yocom1, Mike O. Karl4, Rudgar Neussert4, Soenke Wimmers4, J. Brett Stanton1, Ronald G. Gregg5, Olaf Strauss4, Neal S. Peachey3,6, and Alan D. Marmorstein1,2

1 Department of Ophthalmology and Vision Science and 2 Optical Sciences Center, University of Arizona, Tucson, AZ 85711
3 Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
4 Experimentelle Ophthalmologie Universitaetsklinkum Hamburg-Eppendorf, Hamburg, Germany
5 Biochemistry and Molecular Biology, Ophthalmology and Visual Science, University of Louisville, KY 40202
6 Research Service, Cleveland VA Medical Center, Cleveland, OH 44106

Correspondence to Alan D. Marmorstein: amarmorstein{at}eyes.arizona.edu

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 ß-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the ß4 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 ß4 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.

Abbreviations used in this paper: ADVIRC, autosomal dominant vitreoretinal choroidopathy; AVMD, adult onset vitelliform dystrophy; BMD, Best vitelliform macular dystrophy; DC, direct current; EOG, electrooculogram; ERG, electroretinogram; FO, fast oscillation; LP, light peak; LPS, LP substance; VDCC, voltage-dependent calcium channel; wt, wild-type.


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