Bestrophins and retinopathies

Invited Review

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.

Keywords

Bestrophin Best vitelliform macular dystrophy Chloride channel Retinopathies 

References

  1. 1.
    Acharya JK, Dasgupta U, Rawat SS, Yuan C, Sanxaridis PD, Yonamine I, Karim P, Nagashima K, Brodsky MH, Tsunoda S, Acharya U (2008) Cell-nonautonomous function of ceramidase in photoreceptor homeostasis. Neuron 57:69–79CrossRefPubMedGoogle Scholar
  2. 2.
    Arden GB (1962) Alterations in the standing potential of the eye associated with retinal disease. Trans Ophthalmol Soc U K 82:63–72PubMedGoogle Scholar
  3. 3.
    Bakall B, Radu RA, Stanton JB, Burke JM, McKay BS, Wadelius C, Mullins RF, Stone EM, Travis GH, Marmorstein AD (2007) Enhanced accumulation of A2E in individuals homozygous or heterozygous for mutations in BEST1 (VMD2). Exp Eye Res 85:34–43CrossRefPubMedGoogle Scholar
  4. 4.
    Barak A, Morse LS, Goldkorn T (2001) Ceramide: a potential mediator of apoptosis in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 42:247–254PubMedGoogle Scholar
  5. 5.
    Barro-Soria R, Aldehni F, Almaca J, Witzgall R, Schreiber R, Kunzelmann K (2010) ER-localized bestrophin 1 activates Ca(2+)-dependent ion channels TMEM16A and SK4 possibly by acting as a counterion channel. Pflugers Arch 459:485–497CrossRefPubMedGoogle Scholar
  6. 6.
    Bok D (2002) New insights and new approaches toward the study of age-related macular degeneration. Proc Natl Acad Sci U S A 99:14619–14621CrossRefPubMedGoogle Scholar
  7. 7.
    Boon CJ, Klevering BJ, Leroy BP, Hoyng CB, Keunen JE, den Hollander AI (2009) The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res 28:187–205CrossRefPubMedGoogle Scholar
  8. 8.
    Bosl MR, Stein V, Hubner C, Zdebik AA, Jordt SE, Mukhopadhyay AK, Davidoff MS, Holstein AF, Jentsch TJ (2001) Male germ cells and photoreceptors, both dependent on close cell–cell interactions, degenerate upon ClC-2 Cl(-) channel disruption. EMBO J 20:1289–1299CrossRefPubMedGoogle Scholar
  9. 9.
    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 (2008) Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet 82:19–31CrossRefPubMedGoogle Scholar
  10. 10.
    Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ (2008) TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science 322:590–594CrossRefPubMedGoogle Scholar
  11. 11.
    Carter-Dawson LD, LaVail MM (1979) Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy. J Comp Neurol 188:245–262CrossRefPubMedGoogle Scholar
  12. 12.
    Chien LT, Hartzell HC (2007) Drosophila bestrophin-1 chloride current is dually regulated by calcium and cell volume. J Gen Physiol 130:513–534CrossRefPubMedGoogle Scholar
  13. 13.
    Chien LT, Hartzell HC (2008) Rescue of volume-regulated anion current by bestrophin mutants with altered charge selectivity. J Gen Physiol 132:537–546CrossRefPubMedGoogle Scholar
  14. 14.
    Cross HE, Bard L (1974) Electro-oculography in Best's macular dystrophy. Am J Ophthalmol 77:46–50PubMedGoogle Scholar
  15. 15.
    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 (2009) Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. Am J Hum Genet 85:581–592CrossRefPubMedGoogle Scholar
  16. 16.
    de Jong PT (2006) Age-related macular degeneration. N Engl J Med 355:1474–1485CrossRefPubMedGoogle Scholar
  17. 17.
    Eldred GE (1995) Lipofuscin fluorophore inhibits lysosomal protein degradation and may cause early stages of macular degeneration. Gerontology 41:15–28CrossRefPubMedGoogle Scholar
  18. 18.
    Finnemann SC, Leung LW, Rodriguez-Boulan E (2002) The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium. Proc Natl Acad Sci USA 99:3842–3847CrossRefPubMedGoogle Scholar
  19. 19.
    Fischmeister R, Hartzell C (2005) Volume-sensitivity of the bestrophin family of chloride channels. J Physiol 552(2):477–491Google Scholar
  20. 20.
    Fox TE, Han X, Kelly S, Merrill AH, Martin RE, Anderson RE, Gardner TW, Kester M (2006) Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy. Diabetes 55:3573–3580CrossRefPubMedGoogle Scholar
  21. 21.
    Gallemore RP, Griff ER, Steinberg RH (1988) Evidence in support of a photoreceptoral origin for the “light-peak substance”. Invest Ophthalmol Vis Sci 29:566–571PubMedGoogle Scholar
  22. 22.
    Gallemore RP, Hughes BA, Miller SS (1997) Retinal pigment epithelial transport mechanisms and their contributions to the electroretinogram. Prog Retinal Eye Res 16:509–566CrossRefGoogle Scholar
  23. 23.
    Gallemore RP, Hughes BA, Miller SS (1998) Light-induced responses of the retinal pigment epithelium. In: Marmor MF, Wolfensberger TJ (eds) The retinal pigment epithelium. Oxford Univ. Press, Oxford, pp 175–198Google Scholar
  24. 24.
    Gass JDM (1987) Stereoscopic atlas of macular diseases: diagnosis and treatment. Mosby, St. Louis, MOGoogle Scholar
  25. 25.
    Gouras P, Braun K, Ivert L, Neuringer M, Mattison JA (2009) Bestrophin detected in the basal membrane of the retinal epithelium and drusen of monkeys with drusenoid maculopathy. Graefes Arch Clin Exp Ophthalmol 247:1051–1056CrossRefPubMedGoogle Scholar
  26. 26.
    Guziewicz KE, Zangerl B, Lindauer SJ, Mullins RF, Sandmeyer LS, Grahn BH, Stone EM, Acland GM, Aguirre GD (2007) Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease. Invest Ophthalmol Vis Sci 48:1959–1967CrossRefPubMedGoogle Scholar
  27. 27.
    Hannun YA (1996) Functions of ceramide in coordinating cellular responses to stress. Science 274:1855–1859CrossRefPubMedGoogle Scholar
  28. 28.
    Hannun YA, Luberto C (2000) Ceramide in the eukaryotic stress response. Trends Cell Biol 10:73–80CrossRefPubMedGoogle Scholar
  29. 29.
    Hartzell HC, Qu Z (2003) Chloride currents in acutely isolated Xenopus retinal pigment epithelial cells. J Physiol 549:453–469CrossRefPubMedGoogle Scholar
  30. 30.
    Hartzell HC, Qu Z, Putzier I, Artinian L, Chien L-T, Cui Y (2005) Looking chloride channels straight in the eye: bestrophins, lipofuscinosis, and retinal degeneration. Physiol 20:292–302CrossRefGoogle Scholar
  31. 31.
    Hartzell HC, Qu Z, Yu K, Xiao Q, Chien LT (2008) Molecular physiology of bestrophins: multifunctional membrane proteins linked to Best disease and other retinopathies. Physiol Rev 88:639–672CrossRefPubMedGoogle Scholar
  32. 32.
    Hartzell HC, Yu K, Xiao Q, Chien LT, Qu Z (2009) Anoctamin/TMEM16 family members are Ca2+-activated Cl- channels. J Physiol 587:2127–2139CrossRefPubMedGoogle Scholar
  33. 33.
    Hughes BA, Gallemore RP, Miller SS (1998) Transport mechanisms in the retinal pigment epithelium. In: Marmor MF, Wolfensberger TJ (eds) The retinal pigment epithelium. Oxford Univ. Press, Oxford, pp 103–134Google Scholar
  34. 34.
    Jentsch TJ, Poet M, Fuhrmann JC, Zdebik AA (2005) Physiological functions of CLC Cl- channels gleaned from human genetic disease and mouse models. Annu Rev Physiol 67:779–807CrossRefPubMedGoogle Scholar
  35. 35.
    Kolesnick RN, Kronke M (1998) Regulation of ceramide production and apoptosis. Annu Rev Physiol 60:643–665CrossRefPubMedGoogle Scholar
  36. 36.
    Kranjc A, Grillo FW, Rievaj J, Boccaccio A, Pietrucci F, Menini A, Carloni P, Anselmi C (2009) Regulation of bestrophins by Ca2+: a theoretical and experimental study. PLoS One 4:e4672CrossRefPubMedGoogle Scholar
  37. 37.
    Kunzelmann K, Milenkovic VM, Spitzner M, Soria RB, Schreiber R (2007) Calcium-dependent chloride conductance in epithelia: is there a contribution by bestrophin? Pflugers Arch 454:879–889CrossRefPubMedGoogle Scholar
  38. 38.
    Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E, Haussinger D (1998) Functional significance of cell volume regulatory mechanisms. Physiol Rev 78:247–306PubMedGoogle Scholar
  39. 39.
    Linsenmeier RA, Steinberg RH (1982) Origin and sensitivity of the light peak in the intact cat eye. J Physiol 331:653–673PubMedGoogle Scholar
  40. 40.
    Marmorstein AD, Cross HE, Peachey NS (2009) Functional roles of bestrophins in ocular epithelia. Prog Retin Eye Res 28:206–226CrossRefPubMedGoogle Scholar
  41. 41.
    Marmorstein AD, Marmorstein LY, Rayborn M, Wang X, Hollyfield JG, Petrukhin K (2000) 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 97:12758–12763CrossRefPubMedGoogle Scholar
  42. 42.
    Marmorstein LY, McLaughlin PJ, Stanton JB, Yan L, Crabb JW, Marmorstein AD (2002) Bestrophin interacts physically and functionally with protein phosphatase 2A. J Biol Chem 277:30591–30597CrossRefPubMedGoogle Scholar
  43. 43.
    Marmorstein LY, Wu J, McLaughlin P, Yocom J, Karl MO, Neussert R, Wimmers S, Stanton JB, Gregg RG, Strauss O, Peachey NS, Marmorstein AD (2006) The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1). J Gen Physiol 127:577–589CrossRefPubMedGoogle Scholar
  44. 44.
    Marquardt A, Stohr H, Passmore LA, Kramer F, Rivera A, Weber BH (1998) Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). Hum Mol Genet 7:1517–1525CrossRefPubMedGoogle Scholar
  45. 45.
    McCarty NA, O'Neil RG (1992) Calcium signaling in cell volume regulation. Physiol Rev 72:1037–1061PubMedGoogle Scholar
  46. 46.
    Men G, Batioglu F, Ozkan SS, Atilla H, Ozdamar Y, Aslan O (2004) Best's vitelliform macular dystrophy with pseudohypopyon: an optical coherence tomography study. Am J Ophthalmol 137:963–965CrossRefPubMedGoogle Scholar
  47. 47.
    Miller S, Farber D (1984) Cyclic AMP modulation of ion transport across frog retinal pigment epithelium. Measurements in the short-circuit state. J Gen Physiol 83:853–874CrossRefPubMedGoogle Scholar
  48. 48.
    Mohler CW, Fine SL (1981) Long-term evaluation of patients with Best's vitelliform dystrophy. Ophthalmol 88:688–692Google Scholar
  49. 49.
    Mullins RF, Kuehn MH, Faidley EA, Syed NA, Stone EM (2007) Differential macular and peripheral expression of bestrophin in human eyes and its implication for Best disease. Invest Ophthalmol Vis Sci 48:3372–3380CrossRefPubMedGoogle Scholar
  50. 50.
    Niemeyer G (2001) Retinal research using the perfused mammalian eye. Prog Retinal Eye Res 20:289–318CrossRefGoogle Scholar
  51. 51.
    O'Driscoll KE, Leblanc N, Hatton WJ, Britton FC (2009) Functional properties of murine bestrophin 1 channel. Biochem Biophys Res Commun 384:476–481CrossRefPubMedGoogle Scholar
  52. 52.
    Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science 259:1769–1771CrossRefPubMedGoogle Scholar
  53. 53.
    Park H, Oh SJ, Han KS, Woo DH, Park H, Mannaioni G, Traynelis SF, Lee CJ (2009) Bestrophin-1 encodes for the Ca2+-activated anion channel in hippocampal astrocytes. J Neurosci 29:13063–13073CrossRefPubMedGoogle Scholar
  54. 54.
    Peterson WM, Meggyesy CF, Yu KF, Miller SS (1997) Extracellular ATP activates calcium signaling, ion, and fluid transport in retinal pigment epithelium. J Neurosci 17:2324–2337PubMedGoogle Scholar
  55. 55.
    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 (1998) Identification of the gene responsible for Best macular dystrophy. Nat Genet 19:241–247CrossRefPubMedGoogle Scholar
  56. 56.
    Pianta MJ, Aleman TS, Cideciyan AV, Sunness JS, Li Y, Campochiaro BA, Campochiaro PA, Zack DJ, Stone EM, Jacobson SG (2003) In vivo micropathology of Best macular dystrophy with optical coherence tomography. Exp Eye Res 76:203–211CrossRefPubMedGoogle Scholar
  57. 57.
    Pierro L, Tremolada G, Introini U, Calori G, Brancato R (2002) Optical coherence tomography findings in adult-onset foveomacular vitelliform dystrophy. Am J Ophthalmol 134:675–680CrossRefPubMedGoogle Scholar
  58. 58.
    Qu Z, Cheng W, Cui Y, Cui Y, Zheng J (2009) Human disease-causing mutations disrupt an N–C-terminal interaction and channel function of bestrophin 1. J Biol Chem 284:16473–16481CrossRefPubMedGoogle Scholar
  59. 59.
    Qu Z, Chien LT, Cui Y, Hartzell HC (2006) The anion-selective pore of the bestrophins, a family of chloride channels associated with retinal degeneration. J Neurosci 26:5411–5419CrossRefPubMedGoogle Scholar
  60. 60.
    Qu Z, Fischmeister R, Hartzell C (2004) Mouse bestrophin-2 is a bona fide Cl(-) channel: identification of a residue important in anion binding and conduction. J Gen Physiol 123:327–340CrossRefPubMedGoogle Scholar
  61. 61.
    Qu Z, Hartzell C (2004) Determinants of anion permeation in the second transmembrane domain of the mouse bestrophin-2 chloride channel. J Gen Physiol 124:371–382CrossRefPubMedGoogle Scholar
  62. 62.
    Qu Z, Hartzell HC (2008) Bestrophin Cl- channels are highly permeable to HCO3-. Am J Physiol Cell Physiol 294:C1371–C1377CrossRefPubMedGoogle Scholar
  63. 63.
    Ranty ML, Carpentier S, Cournot M, Rico-Lattes I, Malecaze F, Levade T, Delisle MB, Quintyn JC (2009) Ceramide production associated with retinal apoptosis after retinal detachment. Graefes Arch Clin Exp Ophthalmol 247:215–224CrossRefPubMedGoogle Scholar
  64. 64.
    Rosenthal R, Bakall B, Kinnick T, Peachey N, Wimmers S, Wadelius C, Marmorstein A, Strauss O (2006) Expression of bestrophin-1, the product of the VMD2 gene, modulates voltage-dependent Ca2+ channels in retinal pigment epithelial cells. FASEB J 20:178–180PubMedGoogle Scholar
  65. 65.
    Ruvolo PP (2001) Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 15:1153–1160CrossRefPubMedGoogle Scholar
  66. 66.
    Schroeder BC, Cheng T, Jan YN, Jan LY (2008) Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell 134:1019–1029CrossRefPubMedGoogle Scholar
  67. 67.
    Seddon JM, Afshari MA, Sharma S, Bernstein PS, Chong S, Hutchinson A, Petrukhin K, Allikmets R (2001) 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 108:2060–2067CrossRefGoogle Scholar
  68. 68.
    Shaban H, Borras C, Vina J, Richter C (2002) 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 75:99–108CrossRefPubMedGoogle Scholar
  69. 69.
    Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881CrossRefPubMedGoogle Scholar
  70. 70.
    Sun H, Tsunenari T, Yau K-W, Nathans J (2002) The vitelliform macular dystrophy protein defines a new family of chloride channels. Proc Natl Acad Sci USA 99:4008–4013CrossRefPubMedGoogle Scholar
  71. 71.
    Szel A, Rohlich P, Caffe AR, van Veen VT (1996) Distribution of cone photoreceptors in the mammalian retina. Microsc Res Tech 35:445–462CrossRefPubMedGoogle Scholar
  72. 72.
    Tsunenari T, Sun H, Williams J, Cahill H, Smallwood P, Yau K-W, Nathans J (2003) Structure–function analysis of the bestrophin family of anion channels. J Biol Chem 278:41114–41125CrossRefPubMedGoogle Scholar
  73. 73.
    Vedantham V, Ramasamy K (2005) Optical coherence tomography in Best's disease: an observational case report. Am J Ophthalmol 139:351–353CrossRefPubMedGoogle Scholar
  74. 74.
    Wangsa-Wirawan ND, Linsenmeier RA (2003) Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol 121:547–557CrossRefPubMedGoogle Scholar
  75. 75.
    Weng TX, Godley BF, Jin GF, Mangini NJ, Kennedy BG, Yu AS, Wills NK (2002) Oxidant and antioxidant modulation of chloride channels expressed in human retinal pigment epithelium. Am J Physiol Cell Physiol 283:C839–C849PubMedGoogle Scholar
  76. 76.
    Wills NK, Weng T, Mo L, Hellmich HL, Yu A, Wang T, Buchheit S, Godley BF (2000) Chloride channel expression in cultured human fetal RPE cells: response to oxidative stress. Invest Ophthalmol Vis Sci 41:4247–4255PubMedGoogle Scholar
  77. 77.
    Winkler BS (1986) Buffer dependence of retinal glycolysis and ERG potentials. Exp Eye Res 42:585–593CrossRefPubMedGoogle Scholar
  78. 78.
    Wu J, Marmorstein AD, Peachey NS (2006) Functional abnormalities in the retinal pigment epithelium of CFTR mutant mice. Exp Eye Res 83:424–428CrossRefPubMedGoogle Scholar
  79. 79.
    Wu J, Marmorstein AD, Striessnig J, Peachey NS (2007) Voltage-dependent calcium channel CaV1.3 subunits regulate the light peak of the electroretinogram. J Neurophysiol 97:3731–3735CrossRefPubMedGoogle Scholar
  80. 80.
    Xiao Q, Prussia A, Yu K, Cui YY, Hartzell HC (2008) Regulation of bestrophin Cl channels by calcium: role of the C terminus. J Gen Physiol 132:681–692CrossRefPubMedGoogle Scholar
  81. 81.
    Xiao Q, Yu K, Cui YY, Hartzell HC (2009) Dysregulation of human bestrophin-1 by ceramide-induced dephosphorylation. J Physiol 587:4379–4391CrossRefPubMedGoogle Scholar
  82. 82.
    Yamada Y, Tian J, Yang Y, Cutler RG, Wu T, Telljohann RS, Mattson MP, Handa JT (2008) Oxidized low density lipoproteins induce a pathologic response by retinal pigmented epithelial cells. J Neurochem 105:1187–1197CrossRefPubMedGoogle Scholar
  83. 83.
    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 (2008) TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature 455:1210–1215CrossRefPubMedGoogle Scholar
  84. 84.
    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 (2004) Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Invest Ophthalmol Vis Sci 45:3683–3689CrossRefPubMedGoogle Scholar
  85. 85.
    Yu K, Cui Y, Hartzell HC (2006) The bestrophin mutation A243V, linked to adult-onset vitelliform macular dystrophy, impairs its chloride channel function. Invest Ophthalmol Vis Sci 47:4956–4961CrossRefPubMedGoogle Scholar
  86. 86.
    Yu K, Qu Z, Cui Y, Hartzell HC (2007) Chloride channel activity of bestrophin mutants associated with mild or late-onset macular degeneration. Invest Ophthalmol Vis Sci 48:4694–4705CrossRefPubMedGoogle Scholar
  87. 87.
    Yu K, Xiao Q, Cui G, Lee A, Hartzell HC (2008) The Best disease-linked Cl- channel hBest1 regulates Ca V 1 (L-type) Ca2+ channels via src-homology-binding domains. J Neurosci 28:5660–5670CrossRefPubMedGoogle Scholar
  88. 88.
    Yu K, Lujan R, Marmorstein A, Gabriel S, Hartzell HC (2010) Bestrophine-2 mediates bicarbonate transport by goblet cells in mammalian colon. J Clin Invest 120(5), in pressGoogle Scholar
  89. 89.
    Zhang Y, Stanton JB, Wu J, Yu K, Hartzell HC, Peachey NS, Marmorstein LY, Marmorstein AD (2010) Suppression of Ca2+ signaling in a mouse model of Best disease. Hum Mol Genet 19:1108–1118. http://hmg.oxfordjournals.org/cgi/content/full/ddp583v2 Google Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Cell Biology and Center for Neurodegenerative DiseaseEmory University School of MedicineAtlantaUSA

Personalised recommendations