Modulation of the gating of ClC‐1 by S‐(–) 2‐(4‐chlorophenoxy) propionic acid

Aromataris, Edoardo; Astill, David; Rychkov, Grigori Y.; Bryant, S. H.; Bretag, Allan H.; Roberts, Michael L.

doi:10.1038/sj.bjp.0702459

Cited by 36 publications

(42 citation statements)

References 36 publications

(58 reference statements)

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“…The efficacy of CPP depends on the internal Cl − concentration in a manner that is consistent with a competition between Cl − and CPP for the occupation of the same or closely located sites (Pusch et al 2001). The action of these blockers is voltage dependent, reducing currents at negative voltages but leaving them almost unaltered at positive voltages (Aromataris et al 1999). The voltage dependence arises from a state‐dependent binding, with closed channels having higher affinity for the blocker compared to open channels (Pusch et al 2001).…”

Section: Pharmacology Of Clc Channels – Mechanism Of Action Of P‐chlomentioning

confidence: 99%

Channel or transporter? The CLC saga continues

Pusch¹,

Zifarelli²,

Murgia³

et al. 2005

Experimental Physiology

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It was recently shown that the putative bacterial Cl -channel, ClC-ec1, is in reality a Cl --H + antiporter. Our group has now shown that this is also the case for two human CLCs, ClC-4 and ClC-5. We found that the flux of Cl -in one direction is stoichiometrically coupled to the movement of protons in the opposite direction, unveiling a behaviour that is typical of a transporter rather than a channel. This discovery will surely stimulate further research to elucidate the molecular elements responsible for the behaviour as a transporter. On the physiological level, the antiport activity of ClC-4/ClC-5 must lead to a review of the role of CLC proteins in intracellular compartments. Small organic molecules have been extremely useful tools for studying ion channels and many commercial drugs target specific ion channel proteins. Several blockers have been found to inhibit the plasma membrane-localized CLC channels ClC-0, ClC-1 and ClC-Ka. These compounds include 9-anthracene-carboxylic acid (9-AC), p-chlorophenoxy-propionic acid (CPP) and its derivatives, and 4,4 -diisothiocyanatostilbene-2,2 -disulphonic acid (DIDS). Two different binding sites have been identified, one extracellular and one intracellular. However, high-affinity ligands for most CLC proteins are still missing. Apart from being useful biophysical tools, such drugs may provide a way to modulate protein function in vivo. With these tasks to be accomplished, it is definitely an exciting time in the chloride transport field.

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Section: Pharmacology Of Clc Channels – Mechanism Of Action Of P‐chlomentioning

confidence: 99%

Channel or transporter? The CLC saga continues

Pusch¹,

Zifarelli²,

Murgia³

et al. 2005

Experimental Physiology

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“…A drug that increases the open probability could then increase the Cl conductance of the skeletal muscle and abolish the hyperexcitability. The pharmacological agents that interfere most strongly with CLC-1 are 9-anthracene carboxylic acid (9AC) and the S( ) enantiomer of p-chloro-phenoxy-propionic acid (CPP), both of which inhibit the muscle Cl conductance and CLC-1with an apparent affinity in the 10-50 µM range [Palade and Barchi, 1977;De Luca et al, 1992;Steinmeyer et al, 1991b;Aromataris et al, 1999;Pusch et al, 2000]. CPP and also 9AC are most likely open channel blockers that, in addition, reduce the open probability by impeding channel opening of closed, drug-bound channels [Pusch et al, 2001;Accardi and Pusch, unpublished observations].…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Myotonia caused by mutations in the muscle chloride channel geneCLCN1

2002

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Pure non-syndromic, non-dystrophic myotonia in humans is caused by mutations in the genes coding for the skeletal muscle sodium channel (SCN5A) or the skeletal muscle chloride channel (CLCN1) with similar phenotypes. Chloride-channel myotonia can be dominant (Thomsen-type myotonia) or recessive (Becker-type myotonia). More than 60 myotonia-causing mutations in the CLCN1 gene have been identified, with only a few of them being dominant. A common phenotype of dominant mutations is a dominant negative effect of mutant subunits in mutant-WT heterodimers, causing a large shift of the steady-state open probability voltage-dependence towards more positive, unphysiological voltages. The study of the properties of disease causing mutations has helped in understanding the functional properties of the CLC-1 channel that is part of a nine-member gene family of chloride channels. The large body of knowledge obtained for CLC-1 may also help to better understand the other CLC channels, three of which are also involved in genetic diseases.

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“…To date, the only substances available are derivatives of the 2-(p-chlorophenoxy)propionic acid (CPP), which are molecules that stereoselectively modulate the macroscopic resting Cl Ϫ conductance (gCl) of skeletal muscle as well as the activity of CLC-1, the muscle Cl Ϫ channel underlying gCl (Bettoni et al, 1987;Aromataris et al, 1999). As for native gCl, the S(Ϫ)-enantiomer is the most potent CPP-enantiomer able to block the currents of heterologously expressed human CLC (hCLC)-1 interfering with channel gating by acting from the intracellular side (Pusch et al, 2000).…”

Section: The Movement Of CLmentioning

confidence: 99%

Molecular Requisites for Drug Binding to Muscle CLC-1 and Renal CLC-K Channel Revealed by the Use of Phenoxy-Alkyl Derivatives of 2-(p-Chlorophenoxy)Propionic Acid

et al. 2002

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CLC channels are a gene family of Cl Ϫ channels that serve a variety of functions, several of which are involved in genetic diseases. Few specific ligands of CLC channels are known that could be useful as pharmacological tools or potential drugs. We synthesized various derivatives of 2-(p-chlorophenoxy)propionic acid, the S(Ϫ)-enantiomer of which is a specific blocker of the muscle channel CLC-1. In particular, compounds with different alkyl or phenoxy-alkyl groups on the chiral center, isosteres of the oxygen in the aryloxy moiety, or bioisosteres of the carboxy function were prepared. We found that compounds containing a phenoxy and a phenoxy-alkyl group on the chiral center (bis-phenoxy derivatives) specifically inhibited renal CLC-K channels from the extracellular side with an affinity in the 150-M range and with almost no effect on other CLC channels when applied from the outside. Surprisingly, the same substances inhibited CLC-1 from the intracellular side in a voltage-dependent manner with an apparent K D of Ͻ5 M at Ϫ140 mV, thus being the most potent blockers of a CLC channel known so far. Although the chlorine atom in paraposition of the second phenoxy group was essential for inhibition of CLC-K channels from the outside, it could be substituted by a methoxy group without changing the potency of block for CLC-1 from the inside. These newly identified substances provide powerful tools for studying the structure-function relationship and the physiological role of CLC channels and may represent a starting point for the development of useful drugs targeting CLC-K channels.

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Modulation of the gating of ClC‐1 by S‐(–) 2‐(4‐chlorophenoxy) propionic acid

Cited by 36 publications

References 36 publications

Channel or transporter? The CLC saga continues

Channel or transporter? The CLC saga continues

Myotonia caused by mutations in the muscle chloride channel geneCLCN1

Molecular Requisites for Drug Binding to Muscle CLC-1 and Renal CLC-K Channel Revealed by the Use of Phenoxy-Alkyl Derivatives of 2-(p-Chlorophenoxy)Propionic Acid

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