Retinal pigment epithelial transport mechanisms and their contributions to the electroretinogram

Gallemore, Ron P.; Hughes, Bret A.; Miller, Sheldon S.

doi:10.1016/s1350-9462(96)00037-7

Cited by 92 publications

(95 citation statements)

References 192 publications

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“…Because bestrophins are found to possess chlorine channel function (2), the mechanism for Best disease has been considered to be a loss of chlorine channel function in retinal pigment epithelia when the channel protein is mutated. Consistent with this idea, a hallmark diagnostic feature of Best disease is the slow light peak reduction in electrooculogram (31), which is thought to reflect a decrease in the chlorine conductance in the basolateral membrane of the retinal pigment epithelia (32). Bestrophin 1 protein has been shown to be expressed in the basolateral membrane of retinal pigment epithelia (33).…”

Section: Functional Roles Of N-c-terminal Interaction Between Hbest1mentioning

confidence: 87%

Human Disease-causing Mutations Disrupt an N-C-terminal Interaction and Channel Function of Bestrophin 1

Cheng

Cui

et al. 2009

Journal of Biological Chemistry

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Mutations in the human bestrophin 1 (hBest1) chloride channel cause Best vitelliform macular dystrophy. Although mutations in its transmembrane domains were found to alter biophysical properties of the channel, the mechanism for disease-causing mutations in its N and C termini remains elusive. We hypothesized that these mutations lead to channel dysfunction through disruption of an N-C-terminal interaction. Here, we present data demonstrating that hBest1 N and C termini indeed interact both in vivo and in vitro. In addition, using a spectrum-based fluorescence resonance energy transfer method, we showed that functional hBest1 channels in the plasma membrane were multimers. Disease-causing mutations in the N terminus (R19C, R25C, and K30C) and the C terminus (G299E, D301N, and D312N) caused channel dysfunction and disruption of the N-C interaction. Consistent with the functional and biochemical results, mutants D301N and D312N clearly reduced fluorescence resonance energy transfer signal, indicating that the N-C interaction was indeed perturbed. These results suggest that hBest1 functions as a multimer in the plasma membrane, and disruption of the N-C interaction by mutations leads to hBest1 channel dysfunction.

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Section: Functional Roles Of N-c-terminal Interaction Between Hbest1mentioning

confidence: 87%

Human Disease-causing Mutations Disrupt an N-C-terminal Interaction and Channel Function of Bestrophin 1

Cheng

Cui

et al. 2009

Journal of Biological Chemistry

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“…Various stimuli have been shown to induce the release of intracellular Ca 2+ through the activation of inositol-1,4,5-trisphosphate receptors. These include growth factors [15], carbachol [34], histamine [35], and ATP which is speculated to be the "light-peak substance" [36,37]. Accordingly, Orai channels in RPE cells provide a way to refill intracellular Ca 2+ stores after activation of ryanodine or inositol-1,4,5-trisphosphate receptors.…”

Section: Discussionmentioning

confidence: 99%

Expression of Orai genes and ICRAC activation in the human retinal pigment epithelium

Cordeiro

Strauß

2010

Graefes Arch Clin Exp Ophthalmol

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With these data we show a new Ca²(+) entry pathway linked to the Ca²(+)/inositolphosphate second-messenger system in RPE cells which help to further understand regulatory pathways of agonists. The expression of Orai channels enables the RPE cells to generate sustained or repetitive Ca²(+) signals as they are known to be induced by different stimuli like ATP, bFGF, and the stimulation with photoreceptor outer segments.

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“…The slow light peak is thought to reflect a Cl conductance in the basolateral membrane of the retinal pigment epithelium (Gallemore et al, 1997). Because Best1 is localized at the basolateral membrane of the RPE (Marmorstein et al, 2000;Bakall et al, 2003), the idea that Best1 is responsible for the basolateral Cl conductance is particularly attractive.…”

Section: Introductionmentioning

confidence: 99%

The Anion-Selective Pore of the Bestrophins, a Family of Chloride Channels Associated with Retinal Degeneration

Chien²,

Cui³

et al. 2006

J. Neurosci.

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Mutations in human bestrophin-1 (VMD2) are genetically linked to a juvenile form of macular degeneration and autosomal dominant vitreoretinochoroidopathy. Recently, it has been proposed that bestrophins are Cl Ϫ channels and that the putative second transmembrane domain participates in forming the bestrophin pore. However, the structural determinants of Cl Ϫ ion permeation through the channel pore are not known. Here we systematically replaced every amino acid in mouse bestrophin-2 (mBest2) between positions 69 and 104 with cysteine. We then measured the effects on the relative permeability and conductance of the channel to Cl Ϫ and SCN Ϫ (thiocyanate) and determined the accessibility of the cysteine-substituted amino acids to extracellularly applied, membrane-impermeant sulfhydryl reagents. Unlike K ϩ channels, the amino acids forming the mBest2 selectivity filter are not discretely localized but are distributed over ϳ20 amino acids within the transmembrane domain. Cysteine-substituted amino acids in the selectivity filter are easily accessible to extracellularly applied sulfhydryl reagents and select for anionic sulfhydryl reagents over cationic ones. Understanding the structure of the anion conduction pathway of bestrophins provides insights into how mutations produce channel dysfunction and may provide important information for development of therapeutic strategies for treating macular degeneration.

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Retinal pigment epithelial transport mechanisms and their contributions to the electroretinogram

Cited by 92 publications

References 192 publications

Human Disease-causing Mutations Disrupt an N-C-terminal Interaction and Channel Function of Bestrophin 1

Human Disease-causing Mutations Disrupt an N-C-terminal Interaction and Channel Function of Bestrophin 1

Expression of Orai genes and ICRAC activation in the human retinal pigment epithelium

The Anion-Selective Pore of the Bestrophins, a Family of Chloride Channels Associated with Retinal Degeneration

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