Regulation of a Human Chloride Channel

Ho, Melisa W.Y.; Kaetzel, Marcia A.; Armstrong, David M.; Shears, Stephen B.

doi:10.1074/jbc.m101128200

Cited by 65 publications

(23 citation statements)

References 37 publications

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“…Yet stimulus-dependent, Ins(1,4,5)P 3 -coupled increases in Ins(3,4,5,6)P 4 levels are a ubiquitous phenomenon (2). Now we have increased our understanding of the biological significance of Ins (3,4,5,6)P 4 by showing that it also regulates insulin granule acidification. We conclude that charge neutralization by ClC3 (the species of ClC in insulin granules, Ref.…”

Section: Resultsmentioning

confidence: 99%

“…Prior to this report, Ins(3,4,5,6)P 4 was only known to be physiologically active as an inhibitor of salt and fluid secretion from epithelial cells (6,7) through modulation of at least some members of the CLCA family (3,5,14). Yet stimulus-dependent, Ins(1,4,5)P 3 -coupled increases in Ins(3,4,5,6)P 4 levels are a ubiquitous phenomenon (2).…”

Section: Resultsmentioning

confidence: 99%

“…When this observation was first made, Ins(3,4,5,6)P 4 had no known physiological function and was deemed to be an "orphan" signal (2). Subsequently Ins (3,4,5,6)P 4 was shown to inhibit the conductance through Ca 2ϩ -activated Cl Ϫ channels (CLCAs) in the plasma membrane (3)(4)(5). However, this signaling paradigm has, to date, seemed restricted to epithelial salt and fluid secretion (6,7).…”

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Inositol 3,4,5,6-Tetrakisphosphate Inhibits Insulin Granule Acidification and Fusogenic Potential

Renström¹,

Ivarsson²,

Shears³

2002

Journal of Biological Chemistry

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ClC Cl؊ channels in endosomes, synaptosomes, lysosomes, and ␤-cell insulin granules provide charge neu- . We now ascribe just such a regulatory function to the increases in cellular levels of inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P 4 ) that inevitably accompany activation of the ubiquitous Ins(1,4,5)P 3 signaling pathway. We used confocal imaging to record insulin granule acidification in single mouse pancreatic ␤-cells. Granule acidification was reduced by perfusion of single cells with 10 M Ins(3,4,5,6)P 4 (the concentration following receptor activation), whereas at 1 M ("resting" levels), Ins(3,4,5,6)P 4 was ineffective. This response to Ins(3,4,5,6)P 4 was not mimicked by 100 M Ins(1,4,5,6)P 4 or by 100 M Ins(1,3,4,5,6)P 5 . Ins(3,4,5,6)P 4 did not affect granular H ؉ -ATPase activity or H ؉ leak, indicating that Ins(3,4,5,6)P 4 instead inhibited charge neutralization by ClC. The Ins(3,4,5,6)P 4 -mediated inhibition of vesicle acidification reduced exocytic release of insulin as determined by whole-cell capacitance recordings. This may impinge upon type 2 diabetes etiology. Regulatory control over vesicle acidification by this negative signaling pathway in other cell types should be considered.Elevations in Ins(3,4,5,6)P 4 1 levels are ubiquitously coupled to stimulus-dependent activation of the Ins(1,4,5)P 3 signaling pathway (1, 2). When this observation was first made, Ins(3,4,5,6)P 4 had no known physiological function and was deemed to be an "orphan" signal (2). Subsequently Ins(3,4,5,6)P 4 was shown to inhibit the conductance through Ca 2ϩ -activated Cl Ϫ channels (CLCAs) in the plasma membrane (3-5). However, this signaling paradigm has, to date, seemed restricted to epithelial salt and fluid secretion (6, 7). This has raised the question as to whether, in other cell types, there can be wider biological significance to receptor-dependent changes in Ins(3,4,5,6)P 4 levels.There are Cl Ϫ channels, which are different from CLCAs, that are expressed in intracellular vesicles, such as endosomes (8), synaptosomes (8), and insulin granules in ␤-cells (9), where they co-localize with H ϩ -ATPases (10 -12). The acidification of the vesicular interior by these H ϩ -ATPases serves a number of important functions, including modulation of certain ligandprotein interactions during endocytosis, enzyme targeting, coupled transport of small molecules, and optimization of proteolytic activities of, for example, prohormone processing enzymes (13,27). It has also been proposed that luminal acidification drives the priming of insulin granules so that they become competent to fuse with the plasma membrane and release their cargo (9). This particular paradigm could be more widely applicable to endocrine and neurotransmitter release.If the vesicle acidification driven by the electrogenic H ϩ -ATPase were not to be charge-compensated, a large transmembrane electrical gradient would develop, and this would then prevent further H ϩ pumping even before a substantial acidification of the vesicular interior could take p...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Inositol 3,4,5,6-Tetrakisphosphate Inhibits Insulin Granule Acidification and Fusogenic Potential

Renström¹,

Ivarsson²,

Shears³

2002

Journal of Biological Chemistry

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“…Both direct activation of the channel by increases in intracellular Ca 2ϩ and indirect activation through Ca 2ϩ -dependent phosphorylation by calmodulin kinase II have been described (2,5). Small conductance CaCC in excised membrane patches of human pancreatic CFPAC cells have been shown to be regulated by Ca 2ϩ , calmodulin kinase II, and inositol 3,4,5,6-tetrakisphosphate (6). CaCC are inhibited by compounds like DIDS and niflumic acid, although these pharmacological tools lack specificity (7).…”

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Bestrophin-1 Enables Ca2+-activated Cl− Conductance in Epithelia

Soria

Spitzner

Schreiber

et al. 2009

Journal of Biological Chemistry

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Epithelial cells express calcium-activated Cl؊ channels of unknown molecular identity. These Cl ؊ channels play a central role in diseases such as secretory diarrhea, polycystic kidney disease, and cystic fibrosis. -activated Cl Ϫ channels (CaCC) 2 are present in almost every cell type examined. Although this type of channel has been studied extensively, the molecular identity of CaCC in epithelial tissues remains a mystery (1, 2). The channels are of small conductance, show outward rectification upon moderate increases in intracellular Ca 2ϩ , and have an anion selectivity of I Ϫ Ͼ Cl Ϫ (3, 4). Both direct activation of the channel by increases in intracellular Ca 2ϩ and indirect activation through Ca 2ϩ -dependent phosphorylation by calmodulin kinase II have been described (2, 5). Small conductance CaCC in excised membrane patches of human pancreatic CFPAC cells have been shown to be regulated by Ca 2ϩ , calmodulin kinase II, and inositol 3,4,5,6-tetrakisphosphate (6). CaCC are inhibited by compounds like DIDS and niflumic acid, although these pharmacological tools lack specificity (7).Molecular candidates for CaCC have been proposed in the past. A family of Ca 2ϩ -activated Cl Ϫ channels (CLCA) has been identified (8, 9). These proteins are involved not only in chloride conductance and epithelial secretion but also in cell-cell adhesion, apoptosis, and cell cycle control. However, detailed structure-function analysis is still missing, and these proteins have a surprisingly low Ca 2ϩ sensitivity (1). Thus, CLCA could be part of a higher Cl Ϫ channel complex (10). The ClC-3 channel has been shown to be regulated by calmodulin kinase II (11). However, ClC-3 is a cytosolic Cl Ϫ channel, located in endosomes, and ClC-3 knock-out animals apparently do not lack CaCC (1).Previous studies demonstrated that bestrophin-1, the product of the vitelliform macular dystrophy (VMD2) gene, is able to form CaCC (12). Mutations in the VMD2 gene cause earlyonset autosomal dominant macular dystrophy of the retina, the so-called Best disease (13). Previous studies detected this channel in the basolateral membrane of the retinal pigment epithelium (14), where it controls the light-peak amplitude in the electrooculogram. Expression of BEST1 was reported to be limited to the retinal pigment epithelium, although it has also been detected in cultured airway epithelial cells (15,16). For the first time, we will provide evidence that endogenously expressed BEST1 causes Ca 2ϩ -activated Cl Ϫ conductance in epithelial tissues. EXPERIMENTAL PROCEDURESUssing Chamber Recordings-Mice (C57BL/6, Charles Rivers Laboratories) were killed under CO 2 narcosis by cervical dislocation. Tissues were put immediately into an ice-cold buffer solution containing 145 mmol/liter NaCl, 3.8 mmol/liter KCl, 5 mmol/liter D-glucose, 1 mmol/liter MgCl 2 , 5 mmol/liter HEPES, and 1.3 mmol/liter calcium gluconate (pH 7.4). After mounting into a perfused micro-Ussing chamber, apical and basolateral surfaces of the epithelium were perfused continuously with buffer solu...

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“…1), which play distinct but critical roles in cellular signaling. [13][14][15][16][17][18][19][20][21][22][23]) D-1 is responsible for the inhibition of the calcium-mediated chloride section. It may have therapeutic implications for diseases like cystic fibrosis and secretory diarrhea.…”

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Diastereoselective Synthesis of D- and L-myo-Inositol 3,4,5,6-Tetrakisphosphates from D-Glucose via Dihydroxylation of (+)-Conduritol B Derivatives

Saito

Shimazawa

Shirai

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Phosphorylated phosphatidyl-myo-inositols and myo-inositol phosphates play important roles as second messengers in intracellular signal transduction. 1) We have previously reported on the synthesis of various lipid analogs as artificial second messengers and biochemical probes. [2][3][4][5][6][7][8][9][10][11][12] Recently, D-and L-myo-inositol 3,4,5,6-tetrakisphosphates (D-1 and L-1) were identified as novel bioactive molecules ( Fig. 1), which play distinct but critical roles in cellular signaling.13-23) D-1 is responsible for the inhibition of the calcium-mediated chloride section. It may have therapeutic implications for diseases like cystic fibrosis and secretory diarrhea. In contrast, L-1 inhibits insulin-like growth factor 1 (IGF-1) induced thymidine incorporation in human breast cancer cells and thus prevents the ability of these cells to grow. Recent studies have revealed that L-1 is also involved in nuclear processes since it is required for gene regulation and may control gene expression. Their mechanisms of action are far from being elucidated but appear to be closely related to the number and position of the phosphate groups on the inositol ring. Thus, a new area of design of anticancer drugs can be envisaged for the future.In order to synthesize suitably protected optically active myo-inositol derivatives with appropriate stereogenic centers, Ferrier rearrangement, 24,25) pinacol coupling [26][27][28][29][30] and ringclosing metathesis (RCM) 12,31) of chiral intermediates derived from precursors such as carbohydrates and tartaric acid derivatives, have been performed in addition to optical resolution 32-34) of racemic myo-inositol derivatives. In this article, we describe the efficient syntheses of both enantiomers of myo-inositol 3,4,5,6-tetrakisphosphates via ring-closing metathesis of 1,7-diene with Grubbs catalyst followed by catalytic OsO 4 dihydroxylation of (ϩ)-conduritol B derivatives (Chart 1).The 1,2-addition of vinylcopper to the known aldehyde (3) 35) derived from D-glucose gave the desired allyl alcohol (4) with high diastereoselectivity (Ͼ99%de). 36) In order to synthesize both D-1 and L-1 from common intermediate 4, its hydroxyl group was protected as 4-methoxybenzyl ether (R 1 ϭPMB, 5a) for D-1 and 2-methoxybenzyl ether (R 1 ϭOMB, 5b) for L-1. Acidic hydrolysis of isopropylidene acetal with aqueous 3 N-H 2 SO 4 in THF, gave an anomeric mixture of the hemiacetal (6a, b), which was subjected to Wittig methylenation to give the 1,7-diene (7a, b). RCM of 7a or 7b using Grubbs catalyst gave the conduritol B derivatives (8a, b) in good yield. To confirm the relative and absolute stereochemistry of 8a, PMB ether was hydrolyzed June 2004 Chem. Pharm. Bull. 52(6) 727-732 (2004) 727 * To whom correspondence should be addressed. Bunkyo-ku, Tokyo 113-0032, Japan. Received February 13, 2004; accepted March 9, 2004; published online March 11, 2004 Syntheses of D-and L-myo-inositol 3,4,5,6-tetrakisphosphates were achieved via diastereoselective 1,2-addition of vinylcopper reagent with t...

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Regulation of a Human Chloride Channel

Cited by 65 publications

References 37 publications

Inositol 3,4,5,6-Tetrakisphosphate Inhibits Insulin Granule Acidification and Fusogenic Potential

Inositol 3,4,5,6-Tetrakisphosphate Inhibits Insulin Granule Acidification and Fusogenic Potential

Bestrophin-1 Enables Ca2+-activated Cl− Conductance in Epithelia

Diastereoselective Synthesis of D- and L-myo-Inositol 3,4,5,6-Tetrakisphosphates from D-Glucose via Dihydroxylation of (+)-Conduritol B Derivatives

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