The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1).
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 beta-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the beta4 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 beta4 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.
Marmorstein
Lihua Y
LY
Department of Ophthalmology and Vision Science, University of Arizona, Tucson 85711, USA.
Wu
Jiang
J
McLaughlin
Precious
P
Yocom
John
J
Karl
Mike O
MO
Neussert
Rudgar
R
Wimmers
Soenke
S
Stanton
J Brett
JB
Gregg
Ronald G
RG
Strauss
Olaf
O
Peachey
Neal S
NS
Marmorstein
Alan D
AD
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000075002:Bestrophins; D002118:Calcium / Q000032:analysis; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology*; D018118:Chloride Channels / Q000502:physiology; D004594:Electrophysiology; D004596:Electroretinography / Q000379:methods*; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007473:Ion Channels; D008027:Light; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
C491856:Best1 protein, mouse; D000075002:Bestrophins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018118:Chloride Channels; D005136:Eye Proteins; D007473:Ion Channels; D009553:Nimodipine; D000255:Adenosine Triphosphate; D002118:Calcium