|
|
|
|
|
|
|
||
ARTICLE |
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.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  A. M. Ebert, C. A. McAnelly, A. V. Handschy, R. L. Mueller, W. A. Horne, and D. M. Garrity Genomic organization, expression, and phylogenetic analysis of Ca2+ channel {beta}4 genes in 13 vertebrate species Physiol Genomics, October 7, 2008; 35(2): 133 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Qu and H. C. Hartzell Bestrophin Cl- channels are highly permeable to HCO3- Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1371 - C1377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yu, Q. Xiao, G. Cui, A. Lee, and H. C. Hartzell The Best Disease-Linked Cl- Channel hBest1 Regulates CaV1 (L-type) Ca2+ Channels via src-Homology-Binding Domains J. Neurosci., May 28, 2008; 28(22): 5660 - 5670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Bakall, P. McLaughlin, J. B. Stanton, Y. Zhang, H. C. Hartzell, L. Y. Marmorstein, and A. D. Marmorstein Bestrophin-2 Is Involved in the Generation of Intraocular Pressure Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1563 - 1570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Hartzell, Z. Qu, K. Yu, Q. Xiao, and L.-T. Chien Molecular Physiology of Bestrophins: Multifunctional Membrane Proteins Linked to Best Disease and Other Retinopathies Physiol Rev, April 1, 2008; 88(2): 639 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Eksandh, G. Adamus, L. Mosgrove, and S. Andreasson Autoantibodies Against Bestrophin in a Patient With Vitelliform Paraneoplastic Retinopathy and a Metastatic Choroidal Malignant Melanoma Arch Ophthalmol, March 1, 2008; 126(3): 432 - 435. [Full Text] [PDF]
|
|
|
|
|
|
S. Wimmers and O. Strauss Basal Calcium Entry in Retinal Pigment Epithelial Cells Is Mediated by TRPC Channels Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5767 - 5772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-T. Chien and H. C. Hartzell Drosophila Bestrophin-1 Chloride Current Is Dually Regulated by Calcium and Cell Volume J. Gen. Physiol., October 29, 2007; 130(5): 513 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yu, Z. Qu, Y. Cui, and H. C. Hartzell Chloride Channel Activity of Bestrophin Mutants Associated with Mild or Late-Onset Macular Degeneration Invest. Ophthalmol. Vis. Sci., October 1, 2007; 48(10): 4694 - 4705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Mullins, M. H. Kuehn, E. A. Faidley, N. A. Syed, and E. M. Stone Differential Macular and Peripheral Expression of Bestrophin in Human Eyes and Its Implication for Best Disease Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 3372 - 3380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Guziewicz, B. Zangerl, S. J. Lindauer, R. F. Mullins, L. S. Sandmeyer, B. H. Grahn, E. M. Stone, G. M. Acland, and G. D. Aguirre Bestrophin Gene Mutations Cause Canine Multifocal Retinopathy: A Novel Animal Model for Best Disease Invest. Ophthalmol. Vis. Sci., May 1, 2007; 48(5): 1959 - 1967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Wu, A. D. Marmorstein, J. Striessnig, and N. S. Peachey Voltage-Dependent Calcium Channel CaV1.3 Subunits Regulate the Light Peak of the Electroretinogram J Neurophysiol, May 1, 2007; 97(5): 3731 - 3735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Marchant, K Yu, K Bigot, O Roche, A Germain, D Bonneau, V Drouin-Garraud, D F Schorderet, F Munier, D Schmidt, et al. New VMD2 gene mutations identified in patients affected by Best vitelliform macular dystrophy J. Med. Genet., March 1, 2007; 44(3): e70 - e70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Milenkovic, A. Rivera, F. Horling, and B. H. F. Weber Insertion and Topology of Normal and Mutant Bestrophin-1 in the Endoplasmic Reticulum Membrane J. Biol. Chem., January 12, 2007; 282(2): 1313 - 1321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yu, Y. Cui, and H. C. Hartzell The Bestrophin Mutation A243V, Linked to Adult-Onset Vitelliform Macular Dystrophy, Impairs Its Chloride Channel Function Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4956 - 4961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-T. Chien, Z.-R. Zhang, and H. C. Hartzell Single Cl- Channels Activated by Ca2+ in Drosophila S2 Cells Are Mediated By Bestrophins J. Gen. Physiol., August 28, 2006; 128(3): 247 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
