1 is caused by mutations in the gene encoding
bestrophin.
2 AS in determining paralog specificity among
bestrophins.
3 Here, we show that
bestrophin 1 (BEST1) but not LRRC8A is crucial for volum
4 Mutations in
bestrophin 1 (BEST1) cause certain eye diseases.
5 Mutations in
bestrophin 1 (BEST1) cause macular degenerative disorder
6 higher expression in the periphery included
bestrophin 1 (BEST1), transcription factor RNA binding m
7 Mutations in the human
bestrophin 1 (hBest1) chloride channel cause Best vitell
8 Human
Bestrophin 1 (hBest1) is a calcium-activated chloride ch
9 n isolates with antibodies specific to human
bestrophin 1 (hBest1) showed that hBest1 protein was exp
10 aob) and abnormally release GABA through the
bestrophin 1 channel.
11 r Ca(2+), comprises four members in mammals (
bestrophin 1-4).
12 Bestrophin-
1 (Best1) and bestrophin-2 (Best2) are two me
13 Mutations in the
bestrophin-
1 (Best1) gene are linked to several kinds of
14 Bestrophin-
1 (BEST1) is a chloride channel expressed in
15 Bestrophin-
1 (Best1) is an anion channel genetically lin
16 Mutations in BEST1, encoding
bestrophin-
1 (Best1), cause Best vitelliform macular dys
17 Human
bestrophin-
1 (hBest1) is a calcium-activated chloride ch
18 in the founding member of the family, human
bestrophin-
1 (hBest1), are responsible for a form of ear
19 ction in the Cl(-) channel function of human
bestrophin-
1 (hBest1), but some patients with BVMD who h
20 y mutations in a chloride ion channel, human
bestrophin-
1 (hBest1).
21 Mutations in human
bestrophin-
1 (VMD2) are genetically linked to a juvenile
22 Ca(V) 1.3 activity in the presence of mutant
bestrophin-
1 and intracellular trafficking of the intera
23 Mutations in
bestrophin-
1 are increasingly recognized as an important
24 n interaction between Ca(V) 1.3 channels and
bestrophin-
1 by immunoprecipitation, Ca(V) 1.3 activity
25 not impair the formation of active wild-type
bestrophin-
1 channels, consistent with the recessive nat
26 1.3 and wild-type bestrophin-1, with mutant
bestrophin-
1 confirmed reduction of Ca(V) 1.3 surface ex
27 Best disease, cotransfection with wild-type
bestrophin-
1 did not impair the formation of active wild
28 L140V and p.D228N) caused mislocalization of
bestrophin-
1 from the basolateral membrane to the cytopl
29 observed in vivo and, thus, implies loss of
bestrophin-
1 function in cmr1-dogs and Y(29)X-affected p
30 Bestrophin-
1 gene (BEST1) mutations are responsible for
31 We propose that ARB is the null phenotype of
bestrophin-
1 in humans.
32 of these mutations is reduced trafficking of
bestrophin-
1 into the plasma membrane.
33 Bestrophin-
1 is preferentially expressed at the basolate
34 One potential role of
Bestrophin-
1 is to trigger an increase in the standing p
35 selected BEST1 mutations, presence of mutant
bestrophin-
1 led to reduced Ca(V) 1.3 activity by modula
36 ruct that would express neurogenin1 from RPE
bestrophin-
1 promoter or neurogenin3 from RPE65 promoter
37 The physiological function of
bestrophin-
1 remains poorly understood although its hete
38 ogously expressed L-type channels and mutant
bestrophin-
1 showed reduced interaction, reduced Ca(V) 1
39 ch-clamping of HEK293 cells transfected with
bestrophin-
1 to measure the Cl(-) current.
40 The BEST1 gene product
bestrophin-
1, a Ca(2+) -dependent anion channel, interac
41 One of these, BEST1, encodes
bestrophin-
1, a protein that when mutated causes Best ma
42 alcium-activated chloride channels (TMEM16A,
Bestrophin-
1, ClC2, and SLC26A9), both features striking
43 The transmembrane protein
bestrophin-
1, encoded by BEST1, is located at the basola
44 Here, we describe four missense mutations in
bestrophin-
1, three that we believe are previously unrep
45 endogenously express Ca(V) 1.3 and wild-type
bestrophin-
1, with mutant bestrophin-1 confirmed reducti
46 hannel activity and cellular localization of
bestrophin-
1.
47 kcc1) and the Ca(2+)-activated anion channel
Bestrophin 2 (Best2), as well as glycoprotein accumulati
48 Here we report cryo-EM structures of bovine
bestrophin-
2 (bBest2) bound and unbound by Ca(2+) at 2.4
49 Bestrophin-1 (Best1) and
bestrophin-
2 (Best2) are two members of the bestrophin f
50 Bestrophin-
2 (BEST2) is a member of the bestrophin famil
51 Bestrophin-
2 (Best2), a putative Cl(-) channel is expres
52 Mice deficient in the bicarbonate channel
bestrophin-
2 (Best2), however, exhibit a lower IOP despi
53 igated the role of a candidate CaCC protein,
bestrophin-
2 (Best2), using Best2-/- mice.
54 matically replaced every amino acid in mouse
bestrophin-
2 (mBest2) between positions 69 and 104 with
55 inantly expressed in RPE/choroid and encodes
bestrophin,
a 580-amino acid protein of 66 kDa.
56 ated in Best macular dystrophy (BMD) encodes
bestrophin,
a 68-kDa basolateral plasma membrane protein
57 1 structurally resembles its animal homolog,
bestrophin,
a Ca(2+)-gated anion channel.
58 Neither wild-type (wt) nor mutant
bestrophin affected the a- or b-waves of the ERG.
59 cells by adenovirus-mediated gene transfer,
bestrophin again was determined by confocal microscopy a
60 VMD2 encodes
bestrophin,
an oligomeric chloride channel that is prefe
61 Protein-protein interaction between
bestrophin and PP2Ac and the structural subunit of PP2A,
62 ltured for 21 days were harvested to compare
bestrophin and RPE65 mRNA expression.
63 phin complex from RPE lysates and identified
bestrophin and the beta-catalytic subunit of protein pho
64 e heart, including CFTR, ClC-2, ClC-3, CLCA,
Bestrophin,
and TMEM16A.
65 Cytoplasmic calcium (Ca(2+)) activates the
bestrophin anion channel, allowing chloride ions to flow
66 The
bestrophins are a newly described family of anion channe
67 Bestrophins are a newly identified family of Cl(-) chann
68 interpreted in terms of the hypotheses that
bestrophins are Cl(-) channels and regulators of Ca sign
69 Recently, it has been proposed that
bestrophins are Cl- channels and that the putative secon
70 This study provides evidence that the
bestrophins are expressed in pancreatic duct cells and,
71 It has been suggested that
bestrophins are multifunctional proteins: they may regul
72 We conclude that
bestrophins are the first molecularly identified Cl- cha
73 We conclude that
bestrophins are volume sensitive and that they could pla
74 andidates as clinically applicable drugs for
bestrophin-
associated diseases/conditions.
75 Bestrophin (
BEST1-4) ligand-gated chloride (Cl(-)) chann
76 Bestrophin calcium-activated chloride channels (CaCCs) r
77 Several chloride channels including TMEM16,
bestrophin,
CFTR, CLCN2 and CLCA1, are also expressed in
78 provide the first structural analysis of the
bestrophin channel family.
79 membrane transport metabolons formed between
bestrophin channels and glutamate metabolic enzymes.
80 Partly because
bestrophin channels have no sequence or structural simil
81 with ARB are presumed to have no functioning
bestrophin channels, significant phenotypic heterogeneit
82 However, unlike
bestrophin channels, VCCN1 lacks the Ca(2+)-binding moti
83 ultiple small molecules as activators of the
bestrophin channels.
84 nction further, we immunoaffinity purified a
bestrophin complex from RPE lysates and identified bestr
85 kage and a approximately 70-80% reduction in
bestrophin current.
86 es in extracellular osmolarity increased the
bestrophin currents slightly, but this was difficult to
87 photoreceptor discs, we investigated whether
bestrophin currents were affected by cell volume.
88 that have a single "selectivity filter," in
bestrophin,
distinct regions of the pore govern anion-vs
89 curs before activation of bestrophin or that
bestrophin does not directly generate the LP conductance
90 The human genome codes for four
bestrophins,
each of which confers a distinctive plasma
91 enes (BST1, BST2, and BST3) belonging to the
bestrophin family have been found to be up-regulated in
92 Best1 and Best2 are two members of the
bestrophin family of anion channels critically involved
93 bestrophin-2 (Best2) are two members of the
bestrophin family of calcium (Ca(2+))-activated chloride
94 The
bestrophin family of calcium (Ca(2+))-activated chloride
95 Bestrophin-2 (BEST2) is a member of the
bestrophin family of calcium-activated anion channels th
96 Recently, the
bestrophin family of proteins have been proposed as a po
97 ls at the apical membrane are members of the
bestrophin family which, like CFTR, are also permeable t
98 Cl- channels, which included members of the
bestrophin family.
99 here that human, Drosophila, and C. elegans
bestrophins form oligomeric chloride channels, and that
100 We cloned two
bestrophins from Xenopus oocytes, which express high lev
101 BEST1 (alias VMD2), the
bestrophin gene causally associated with BMD, was evalua
102 Mutations in the
Bestrophin gene were shown in patients affected with VMD
103 We predict that
bestrophin has six transmembrane domains with the conser
104 In the present study, the expression of
bestrophins has been investigated in the cystic fibrosis
105 Although
bestrophins have been shown clearly to be Cl(-) ion chan
106 There are multiple
bestrophin homologues in the human, Drosophila, and Caen
107 Wt
bestrophin,
however, increased the c-wave and fast oscil
108 Immunohistochemical localization of
bestrophin in a series of 22 unaffected eyes revealed a
109 Bestrophin in human RPE partitioned in the detergent pha
110 ochemistry could not confirm the presence of
Bestrophin in normal human retina.
111 Our findings reveal a novel function of
bestrophin in regulation of Ca(V) channels and suggest a
112 Purified PP2A effectively dephosphorylated
bestrophin in vitro.
113 sensitive control of ion selectivity in the
bestrophins,
including reversal of anion/cation selectiv
114 echanism in C termini may be universal among
bestrophins investigated in the study.
115 f one or two rhodopsins in tandem fused with
bestrophin ion channel domains.
116 Bestrophin is a 68-kDa basolateral plasma membrane prote
117 Recently it was proposed that
bestrophin is a chloride channel responsible for generat
118 These data suggest that
bestrophin is in the signal transduction pathway that mo
119 phosphorylation, and that phosphorylation of
bestrophin is in turn regulated by PP2A.
120 g of macaque and porcine eyes indicated that
bestrophin is localized at the basolateral plasma membra
121 oligomeric chloride channels, and that human
bestrophin is sensitive to intracellular calcium.
122 Bestrophin is thought to be the Cl channel that generate
123 The function of
bestrophin is unknown.
124 Expression of
bestrophins is strongly correlated with the function of
125 Bestrophin isoform 4 (BEST4) is a newly identified subty
126 We propose that these
bestrophin-
like proteins are essential components of the
127 l growth on low CO(2), indicating that the 3
bestrophin-
like proteins may have redundant functions.
128 nal protons are used downstream of thylakoid
bestrophin-
like transporters, probably for the conversio
129 All of the cell lines expressed
bestrophin mRNA by reverse transcription-PCR, but not on
130 ed positive identification of all four human
bestrophin mRNAs.
131 Bestrophin or
bestrophin mutants (W93C or R218C) were overexpressed in
132 Bestrophin or bestrophin mutants (W93C or R218C) were ov
133 explants, but expressed very little mRNA for
bestrophin or RPE65.
134 ing LP amplitude occurs before activation of
bestrophin or that bestrophin does not directly generate
135 model of BMD and to determine the effects of
bestrophin overexpression on the RPE-generated component
136 of bestrophin suggests the possibility that
bestrophin plays a role in generating the altered electr
137 smembrane domain participates in forming the
bestrophin pore.
138 hannels, as was previously thought, and that
bestrophins,
previously prime candidates for Ca(2+)-acti
139 The expression of
bestrophin protein and mRNA was evaluated by immunohisto
140 Topographic differences in the levels of
bestrophin protein may in part explain the propensity fo
141 structure of the anion conduction pathway of
bestrophins provides insights into how mutations produce
142 LP response functions were unaffected by
bestrophin R218C but were significantly altered by bestr
143 Because overexpression of wt
bestrophin shifted luminance response but did not alter
144 -binding domain that is not present in other
bestrophin subtypes.
145 basolateral plasma membrane localization of
bestrophin suggests the possibility that bestrophin play
146 Bestrophin,
the protein product of the VMD gene, has fou
147 ss a range of stimuli were not altered by wt
bestrophin,
though the luminance response function was d
148 Bestrophins (
VMD2, VMD2L1, VMD2L2, and VMD2L3) are a new
149 phin R218C but were significantly altered by
bestrophin W93C.
150 Bestrophin was confined to the basolateral plasma membra
151 Bestrophin was phosphorylated when expressed in RPE-J ce
152 The C-terminal cytoplasmic domain of
bestrophin was sufficient for the interaction with PP2A
153 ne on chromosome 11q13, encoding the protein
bestrophin,
was identified.
154 To characterize
bestrophin,
we initially probed the retinal pigment epit
155 To facilitate studies of
bestrophin,
we produced both rabbit polyclonal and mouse
156 Four of these mutant
bestrophins were coexpressed with the wild type and each
157 The Xenopus
bestrophins were expressed in a variety of tissues.
158 When Xenopus
bestrophins were heterologously expressed in human embry
159 The prediction of enzymatic activity for
bestrophin,
whose gene is mutated in Best macular dystro