The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1)

Lihua Y. Marmorstein, Jiang Wu, Precious McLaughlin, John Yocom, Mike O. Karl, Rudgar Neussert, Soenke Wimmers, J. Brett Stanton, Ronald G. Gregg, Olaf Strauss, Neal S. Peachey, Alan D. Marmorstein

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)577-589
Number of pages13
JournalJournal of General Physiology
Volume127
Issue number5
DOIs
StatePublished - May 2006

ASJC Scopus subject areas

  • Physiology

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    Marmorstein, L. Y., Wu, J., McLaughlin, P., Yocom, J., Karl, M. O., Neussert, R., Wimmers, S., Stanton, J. B., Gregg, R. G., Strauss, O., Peachey, N. S., & Marmorstein, A. D. (2006). The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1). Journal of General Physiology, 127(5), 577-589. https://doi.org/10.1085/jgp.200509473