Bestrophins and retinopathies

Qinghuan Xiao, H Criss Hartzell, Kuai Yu, Qinghuan Xiao, H Criss Hartzell, Kuai Yu

Abstract

Best vitelliform macular dystrophy (BVMD, also called Best's disease) is a dominantly inherited, juvenile-onset form of macular degeneration, which is characterized by abnormal accumulation of yellow pigment in the outer retina and a depressed electro-oculogram light peak (LP). Over 100 disease-causing mutations in human bestrophin-1 (hBest1) are closely linked to BVMD and several other retinopathies. However, the physiological role of hBest1 and the mechanisms of retinal pathology remain obscure partly because hBest1 has been described as a protein with multiple functions including a Ca2+-activated Cl- channel, a Ca2+ channel regulator, a volume-regulated Cl- channel, and a HCO3- channel. This review focuses on how dysfunction of hBest1 is related to the accumulation of yellow pigment and a decreased LP. The dysfunction of hBest1 as a HCO3- channel or a volume-regulated Cl- channel may be associated with defective regulation of the subretinal fluid or phagocytosis of photoreceptor outer segments by retinal pigment epithelium cells, which may lead to fluid and pigment accumulation.

Figures

Fig. 1
Fig. 1
Summary of hBest1 functions. hBest1 is regulated directly by Ca2+ , either through the Ca2+ channel or Gq protein-coupled receptors. hBest1 can be phosphorylated by PKC to regulate channel rundown and dephosphorylated by PP2A activated by ceramide in response to hypertonic stress. hBest1 also inhibits Ca2+ channel though an SH3 binding domain. The intracellular pH can be regulated by hBest1 through its high permeability of HCO3−.
Fig. 2
Fig. 2
The difference in LP in mice and cats. The dc-ERG was recorded in (A) mice to a 7-min light stimulus [43] or (B) in cats to a 10-min light stimulus [39]. The LP is smaller than the C-wave in mice, while the LP in cats is much larger than the C-wave.
Fig. 3
Fig. 3
Expression of hBest1, mBest2 and mBest1 in HEK cells. A. Representative whole-cell current traces recorded from cells transfected with hBest1, mBest1 and mBest2 in presence of 10 μM Ca2+. B. Current amplitudes at 100 mV for hBest1 (n=13), mBest1 (n=10) and mBest2 (n=9).
Fig. 4
Fig. 4
Regulation of hBest1 by Ca2+ channel through an SH3 binding domain. A. Model of functional domains in hBest1. Orange EF1 is an EF hand like structure (D312-D323) critical for Ca2+ binding. The red circle represents an SH3 binding domain, which binds to β subunits of CaV1.3, and inhibits CaV1.3. Two prolines (P330 and P334 in red) are critical for this regulation. Representative current traces (B) and current amplitudes (C) recorded from cells transfected with wild type hBest1 or the 350X mutant with and without CaV1.3. The 350X mutation was made by introducing a stop codon at position 350, thus deleting C-terminus beyond 350, but containing Ca2+ -binding site and the SH3 binding domain. The 350X can not be activated by Ca2+, but this nonfunctional channel was rescued by CaV1.3.
Fig. 5
Fig. 5
Model of hBest1 as a volume regulated Cl− channel in regulation of phagocytosis of POS. A. In the dark, RPE and photoreceptors are not closely attached. B. After the lights turn on, a large amount of osmolytes such glutamate, aspartate and glycine are leaked from POS, accumulate in the extracellular space, and subsequently are transported into RPE. Water is passively absorbed into RPE. C. RPE swells as water enters into the cells. Cell swelling could activate hBest1. D. Opening of hBest1 Cl− channels will cause a Cl− efflux, which could cause the cells to undergo regulatory volume decrease (RVD) and shrink. Photoreceptors are attached to RPE cells following cell swelling and shrinkage. E. Phagocytosis of POS into RPE.

References

    1. Acharya JK, Dasgupta U, Rawat SS, Yuan C, Sanxaridis PD, Yonamine I, Karim P, Nagashima K, Brodsky MH, Tsunoda S, Acharya U. Cell-nonautonomous function of ceramidase in photoreceptor homeostasis. Neuron. 2008;57:69–79.
    1. Arden GB. Alterations in the standing potential of the eye associated with retinal disease. Trans Ophthalmol Soc U K. 1962;82:63–72.
    1. Bakall B, Radu RA, Stanton JB, Burke JM, McKay BS, Wadelius C, Mullins RF, Stone EM, Travis GH, Marmorstein AD. Enhanced accumulation of A2E in individuals homozygous or heterozygous for mutations in BEST1 (VMD2) Exp Eye Res. 2007;85:34–43.
    1. Barak A, Morse LS, Goldkorn T. Ceramide: a potential mediator of apoptosis in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2001;42:247–254.
    1. Barro-Soria R, Aldehni F, Almaca J, Witzgall R, Schreiber R, Kunzelmann K. ER-localized bestrophin 1 activates Ca(2+)-dependent ion channels TMEM16A and SK4 possibly by acting as a counterion channel. Pflugers Arch. 2010;459:485–497.
    1. Bok D. New insights and new approaches toward the study of age-related macular degeneration. Proc Natl Acad Sci U S A. 2002;99:14619–14621.
    1. Boon CJ, Klevering BJ, Leroy BP, Hoyng CB, Keunen JE, den Hollander AI. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res. 2009;28:187–205.
    1. Bosl MR, Stein V, Hubner C, Zdebik AA, Jordt SE, Mukhopadhyay AK, Davidoff MS, Holstein AF, Jentsch TJ. Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(−) channel disruption. EMBO J. 2001;20:1289–1299.
    1. Burgess R, Millar ID, Leroy BP, Urquhart JE, Fearon IM, De BE, Brown PD, Robson AG, Wright GA, Kestelyn P, Holder GE, Webster AR, Manson FD, Black GC. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet. 2008;82:19–31.
    1. Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science. 2008;322:590–594.
    1. Carter-Dawson LD, LaVail MM. Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy. J Comp Neurol. 1979;188:245–262.
    1. Chien LT, Hartzell HC. Drosophila Bestrophin-1 Chloride Current Is Dually Regulated by Calcium and Cell Volume. J Gen Physiol. 2007;130:513–534.
    1. Chien LT, Hartzell HC. Rescue of volume-regulated anion current by bestrophin mutants with altered charge selectivity. J Gen Physiol. 2008;132:537–546.
    1. Cross HE, Bard L. Electro-oculography in Best’s macular dystrophy. Am J Ophthalmol. 1974;77:46–50.
    1. Davidson AE, Millar ID, Urquhart JE, Burgess-Mullan R, Shweikh Y, Parry N, O’Sullivan J, Maher GJ, McKibbin M, Downes SM, Lotery AJ, Jacobson SG, Brown PD, Black GC, Manson FD. Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. Am J Hum Genet. 2009;85:581–592.
    1. de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355:1474–1485.
    1. Eldred GE. Lipofuscin fluorophore inhibits lysosomal protein degradation and may cause early stages of macular degeneration. Gerontology. 1995;41:15–28.
    1. Finnemann SC, Leung LW, Rodriguez-Boulan E. The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium. Proc Natl Acad Sci USA. 2002;99:3842–3847.
    1. Fischmeister R, Hartzell C. Volume-Sensitivity of the Bestrophin Family of Chloride Channels. J Physiol. 2005;552.2:477–491.
    1. Fox TE, Han X, Kelly S, Merrill AH, Martin RE, Anderson RE, Gardner TW, Kester M. Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy. Diabetes. 2006;55:3573–3580.
    1. Gallemore RP, Griff ER, Steinberg RH. Evidence in support of a photoreceptoral origin for the “light-peak substance”. Invest Ophthalmol Vis Sci. 1988;29:566–571.
    1. Gallemore RP, Hughes BA, Miller SS. Retinal pigment epithelial transport mechanisms and their contributions to the electroretinogram. Prog Retinal Eye Res. 1997;16:509–566.
    1. Gallemore RP, Hughes BA, Miller SS. Light-induced responses of the retinal pigment epithelium. In: Marmor MF, Wolfensberger TJ, editors. The Retinal Pigment Epithelium. Oxford Univ. Press; Oxford, UK: 1998. pp. 175–198.
    1. Gass JDM. Stereoscopic Atlas of Macular Diseases: diagnosis and treatment. Mosby; St. Louis, MO: 1987.
    1. Gouras P, Braun K, Ivert L, Neuringer M, Mattison JA. Bestrophin detected in the basal membrane of the retinal epithelium and drusen of monkeys with drusenoid maculopathy. Graefes Arch Clin Exp Ophthalmol. 2009;247:1051–1056.
    1. Guziewicz KE, Zangerl B, Lindauer SJ, Mullins RF, Sandmeyer LS, Grahn BH, Stone EM, Acland GM, Aguirre GD. Bestrophin Gene Mutations Cause Canine Multifocal Retinopathy: A Novel Animal Model for Best Disease. Invest Ophthalmol Vis Sci. 2007;48:1959–1967.
    1. Hannun YA. Functions of ceramide in coordinating cellular responses to stress. Science. 1996;274:1855–1859.
    1. Hannun YA, Luberto C. Ceramide in the eukaryotic stress response. Trends Cell Biol. 2000;10:73–80.
    1. Hartzell HC, Qu Z. Chloride currents in acutely isolated Xenopus retinal pigment epithelial cells. J Physiol. 2003;549:453–469.
    1. Hartzell HC, Qu Z, Putzier I, Artinian L, Chien L-T, Cui Y. Looking chloride channels straight in the eye: bestrophins, lipofuscinosis, and retinal degeneration. Physiol. 2005;20:292–302.
    1. Hartzell HC, Qu Z, Yu K, Xiao Q, Chien LT. Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol Rev. 2008;88:639–672.
    1. Hartzell HC, Yu K, Xiao Q, Chien LT, Qu Z. Anoctamin/TMEM16 family members are Ca2+-activated Cl- channels. J Physiol. 2009;587:2127–2139.
    1. Hughes BA, Gallemore RP, Miller SS. Transport Mechanisms in the Retinal Pigment Epithelium. In: Marmor MF, Wolfensberger TJ, editors. The Retinal Pigment Epithelium. Oxford Univ. Press; Oxford, UK: 1998. pp. 103–134.
    1. Jentsch TJ, Poet M, Fuhrmann JC, Zdebik AA. Physiological functions of CLC Cl-channels gleaned from human genetic disease and mouse models. Annu Rev Physiol. 2005;67:779–807.
    1. Kolesnick RN, Kronke M. Regulation of ceramide production and apoptosis. Annu Rev Physiol. 1998;60:643–665.
    1. Kranjc A, Grillo FW, Rievaj J, Boccaccio A, Pietrucci F, Menini A, Carloni P, Anselmi C. Regulation of bestrophins by Ca2+: a theoretical and experimental study. PLoS One. 2009;4:e4672.
    1. Kunzelmann K, Milenkovic VM, Spitzner M, Soria RB, Schreiber R. Calcium-dependent chloride conductance in epithelia: is there a contribution by Bestrophin? Pflugers Arch. 2007;454:879–889.
    1. Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E, Haussinger D. Functional significance of cell volume regulatory mechanisms. Physiol Rev. 1998;78:247–306.
    1. Linsenmeier RA, Steinberg RH. Origin and sensitivity of the light peak in the intact cat eye. J Physiol. 1982;331:653–673.
    1. Marmorstein AD, Cross HE, Peachey NS. Functional roles of bestrophins in ocular epithelia. Prog Retin Eye Res. 2009;28:206–226.
    1. Marmorstein AD, Marmorstein LY, Rayborn M, Wang X, Hollyfield JG, Petrukhin K. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral membrane of the retinal pigment epithelium. Proc Natl Acad Sci USA. 2000;97:12758–12763.
    1. Marmorstein LY, McLaughlin PJ, Stanton JB, Yan L, Crabb JW, Marmorstein AD. Bestrophin interacts physically and functionally with protein phosphatase 2A. J Biol Chem. 2002;277:30591–30597.
    1. Marmorstein LY, Wu J, McLaughlin P, Yocom J, Karl MO, Neussert R, Wimmers S, Stanton JB, Gregg RG, Strauss O, Peachey NS, Marmorstein AD. The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1) J Gen Physiol. 2006;127:577–589.
    1. Marquardt A, Stohr H, Passmore LA, Kramer F, Rivera A, Weber BH. Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best’s disease) Hum Mol Genet. 1998;7:1517–1525.
    1. McCarty NA, O’Neil RG. Calcium signaling in cell volume regulation. Physiol Rev. 1992;72:1037–1061.
    1. Men G, Batioglu F, Ozkan SS, Atilla H, Ozdamar Y, Aslan O. Best’s vitelliform macular dystrophy with pseudohypopyon: an optical coherence tomography study. Am J Ophthalmol. 2004;137:963–965.
    1. Miller S, Farber D. Cyclic AMP modulation of ion transport across frog retinal pigment epithelium. Measurements in the short-circuit state. J Gen Physiol. 1984;83:853–874.
    1. Mohler CW, Fine SL. Long-term evaluation of patients with Best’s vitelliform dystrophy. Ophthalmol. 1981;88:688–692.
    1. Mullins RF, Kuehn MH, Faidley EA, Syed NA, Stone EM. Differential macular and peripheral expression of bestrophin in human eyes and its implication for best disease. Invest Ophthalmol Vis Sci. 2007;48:3372–3380.
    1. Niemeyer G. Retinal research using the perfused mammalian eye. Prog Retinal Eye Res. 2001;20:289–318.
    1. O’Driscoll KE, Leblanc N, Hatton WJ, Britton FC. Functional properties of murine bestrophin 1 channel. Biochem Biophys Res Commun. 2009;384:476–481.
    1. Obeid LM, Linardic CM, Karolak LA, Hannun YA. Programmed cell death induced by ceramide. Science. 1993;259:1769–1771.
    1. Park H, Oh SJ, Han KS, Woo DH, Park H, Mannaioni G, Traynelis SF, Lee CJ. Bestrophin-1 encodes for the Ca2+-activated anion channel in hippocampal astrocytes. J Neurosci. 2009;29:13063–13073.
    1. Peterson WM, Meggyesy CF, Yu KF, Miller SS. Extracellular ATP activates calcium signaling, ion, and fluid transport in retinal pigment epithelium. J Neurosci. 1997;17:2324–2337.
    1. Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AAB, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C. Identification of the gene responsible for Best macular dystrophy. Nat Genet. 1998;19:241–247.
    1. Pianta MJ, Aleman TS, Cideciyan AV, Sunness JS, Li Y, Campochiaro BA, Campochiaro PA, Zack DJ, Stone EM, Jacobson SG. In vivo micropathology of Best macular dystrophy with optical coherence tomography. Exp Eye Res. 2003;76:203–211.
    1. Pierro L, Tremolada G, Introini U, Calori G, Brancato R. Optical coherence tomography findings in adult-onset foveomacular vitelliform dystrophy. Am J Ophthalmol. 2002;134:675–680.
    1. Qu Z, Cheng W, Cui Y, Cui Y, Zheng J. Human disease-causing mutations disrupt an N-C-terminal interaction and channel function of bestrophin 1. J Biol Chem. 2009;284:16473–16481.
    1. Qu Z, Chien LT, Cui Y, Hartzell HC. The anion-selective pore of the bestrophins, a family of chloride channels associated with retinal degeneration. J Neurosci. 2006;26:5411–5419.
    1. Qu Z, Fischmeister R, Hartzell C. Mouse bestrophin-2 is a bona fide Cl(−) channel: identification of a residue important in anion binding and conduction. J Gen Physiol. 2004;123:327–340.
    1. Qu Z, Hartzell C. Determinants of anion permeation in the second transmembrane domain of the mouse bestrophin-2 chloride channel. J Gen Physiol. 2004;124:371–382.
    1. Qu Z, Hartzell HC. Bestrophin Cl− channels are highly permeable to HCO3−. Am J Physiol Cell Physiol. 2008;294:C1371–C1377.
    1. Ranty ML, Carpentier S, Cournot M, Rico-Lattes I, Malecaze F, Levade T, Delisle MB, Quintyn JC. Ceramide production associated with retinal apoptosis after retinal detachment. Graefes Arch Clin Exp Ophthalmol. 2009;247:215–224.
    1. Rosenthal R, Bakall B, Kinnick T, Peachey N, Wimmers S, Wadelius C, Marmorstein A, Strauss O. Expression of bestrophin-1, the product of the VMD2 gene, modulates voltage-dependent Ca2+ channels in retinal pigment epithelial cells. FASEB J. 2006;20:178–180.
    1. Ruvolo PP. Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia. 2001;15:1153–1160.
    1. Schroeder BC, Cheng T, Jan YN, Jan LY. Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008;134:1019–1029.
    1. Seddon JM, Afshari MA, Sharma S, Bernstein PS, Chong S, Hutchinson A, Petrukhin K, Allikmets R. Assessment of mutations in the best macular dystrophy (VMD2) gene in patients with adult-onset foveomacular vitelliform dystrophy, age-related maculopathy, and bull’s-eye maculopathy. Ophthalmol. 2001;108:2060–2067.
    1. Shaban H, Borras C, Vina J, Richter C. Phosphatidylglycerol potently protects human retinal pigment epithelial cells against apoptosis induced by A2E, a compound suspected to cause age-related macula degeneration. Exp Eye Res. 2002;75:99–108.
    1. Strauss O. The Retinal Pigment Epithelium in Visual Function. Physiol Rev. 2005;85:845–881.
    1. Sun H, Tsunenari T, Yau K-W, Nathans J. The vitelliform macular dystrophy protein defines a new family of chloride channels. Proc Natl Acad Sci USA. 2002;99:4008–4013.
    1. Szel A, Rohlich P, Caffe AR, van VT. Distribution of cone photoreceptors in the mammalian retina. Microsc Res Tech. 1996;35:445–462.
    1. Tsunenari T, Sun H, Williams J, Cahill H, Smallwood P, Yau K-W, Nathans J. Structure-function analysis of the bestrophin family of anion channels. J Biol Chem. 2003;278:41114–41125.
    1. Vedantham V, Ramasamy K. Optical coherence tomography in Best’s disease: an observational case report. Am J Ophthalmol. 2005;139:351–353.
    1. Wangsa-Wirawan ND, Linsenmeier RA. Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol. 2003;121:547–557.
    1. Weng TX, Godley BF, Jin GF, Mangini NJ, Kennedy BG, Yu AS, Wills NK. Oxidant and antioxidant modulation of chloride channels expressed in human retinal pigment epithelium. Am J Physiol Cell Physiol. 2002;283:C839–C849.
    1. Wills NK, Weng T, Mo L, Hellmich HL, Yu A, Wang T, Buchheit S, Godley BF. Chloride channel expression in cultured human fetal RPE cells: response to oxidative stress. Invest Ophthalmol Vis Sci. 2000;41:4247–4255.
    1. Winkler BS. Buffer dependence of retinal glycolysis and ERG potentials. Exp Eye Res. 1986;42:585–593.
    1. Wu J, Marmorstein AD, Peachey NS. Functional abnormalities in the retinal pigment epithelium of CFTR mutant mice. Exp Eye Res. 2006;83:424–428.
    1. Wu J, Marmorstein AD, Striessnig J, Peachey NS. Voltage-Dependent Calcium Channel CaV1.3 Subunits Regulate the Light Peak of the Electroretinogram. J Neurophysiol. 2007;97:3731–3735.
    1. Xiao Q, Prussia A, Yu K, Cui YY, Hartzell HC. Regulation of bestrophin Cl channels by calcium: role of the C terminus. J Gen Physiol. 2008;132:681–692.
    1. Xiao Q, Yu K, Cui YY, Hartzell HC. Dysregulation of human bestrophin-1 by ceramide-induced dephosphorylation. J Physiol. 2009;587:4379–4391.
    1. Yamada Y, Tian J, Yang Y, Cutler RG, Wu T, Telljohann RS, Mattson MP, Handa JT. Oxidized low density lipoproteins induce a pathologic response by retinal pigmented epithelial cells. J Neurochem. 2008;105:1187–1197.
    1. Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature. 2008;455:1210–1215.
    1. Yardley J, Leroy BP, Hart-Holden N, Lafaut BA, Loeys B, Messiaen LM, Perveen R, Reddy MA, Bhattacharya SS, Traboulsi E, Baralle D, De Laey JJ, Puech B, Kestelyn P, Moore AT, Manson FD, Black GC. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC) Invest Ophthalmol Vis Sci. 2004;45:3683–3689.
    1. Yu K, Cui Y, Hartzell HC. The bestrophin mutation A243V, linked to adult-onset vitelliform macular dystrophy, impairs its chloride channel function. Invest Ophthalmol Vis Sci. 2006;47:4956–4961.
    1. Yu K, Qu Z, Cui Y, Hartzell HC. Chloride channel activity of bestrophin mutants associated with mild or late-onset macular degeneration. Invest Ophthalmol Vis Sci. 2007;48:4694–4705.
    1. Yu K, Xiao Q, Cui G, Lee A, Hartzell HC. The best disease-linked Cl− channel hBest1 regulates Ca V 1 (L-type) Ca2+ channels via src-homology-binding domains. J Neurosci. 2008;28:5660–5670.
    1. Yu K, Lujan R, Marmorstein A, Gabriel S, Hartzell HC. Bestrophine-2 mediates bicarbonate transport by goblet cells in mammalian colon. J Clin Invest. 2010;120(5) in press.
    1. Zhang Y, Stanton JB, Wu J, Yu K, Hartzell HC, Peachey NS, Marmorstein LY, Marmorstein AD. Suppression of Ca2+ Signaling in a Mouse Model of Best Disease. Hum Mol Genet. 2010;19:1108–1118. .

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