Proton-coupled gating in chloride channels

Lísal, Jiří; Maduke, Merritt

doi:10.1098/rstb.2008.0123

Cited by 33 publications

(33 citation statements)

References 43 publications

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“…Intriguingly this glutamate residue is not conserved in CmClC antiporters either, suggesting the existence of an alternate H þ transport pathway 13 . Lisal and Maduke 53 have suggested that another highly conserved glutamate residue on helix H, E291 ( Supplementary Fig. S1), may be part of the H þ transport pathway.…”

Section: Discussionmentioning

confidence: 99%

Molecular determinants of common gating of a ClC chloride channel

Bennetts

Parker

2013

Nat Commun

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Uniquely, the ClC family harbours dissipative channels and anion/H þ transporters that share unprecedented functional characteristics. ClC-1 channels are homodimers in which each monomer supports an identical pore carrying three anion-binding sites. Transient occupancy of the extracellular binding site by a conserved glutamate residue, E232, independently gates each pore. A common gate, the molecular basis of which is unknown, closes both pores simultaneously. Mutations affecting common gating underlie myotonia congenita in humans. Here we show that the common gate likely occludes the channel pore via interaction of E232 with a highly conserved tyrosine, Y578, at the central anion-binding site. We also identify structural linkages important for coordination of common gating between subunits and modulation by intracellular molecules. Our data reveal important molecular determinants of common gating of ClC channels and suggest that the molecular mechanism is an evolutionary vestige of coupled anion/H þ transport.

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Section: Discussionmentioning

confidence: 99%

Molecular determinants of common gating of a ClC chloride channel

Bennetts

Parker

2013

Nat Commun

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“…Thus the asymmetry of ClC-0 gating is driven by the proton gradient, and not the gradient for Cl − . These authors suggest that this is remnant of evolution of ion channels from an ancestral transporter (64, 66). This idea is strengthened by data that other ClC channels show pH-dependent changes in activity.…”

Section: A Thin Line Between Channels and Transportersmentioning

confidence: 99%

Chloride Channels: Often Enigmatic, Rarely Predictable

Duran

Thompson

Xiao

et al. 2010

Annu. Rev. Physiol.

295

278

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Until recently, anion (Cl − ) channels have received considerably less attention than cation channels. One reason for this may be that many Cl − channels perform functions that might be considered cell biological, like fluid secretion and cell volume regulation, whereas cation channels have historically been associated with cellular excitability that typically happens more rapidly. In this review, we discuss the recent explosion of interest in Cl − channels with special emphasis on new and often surprising developments over the last 5 years. This is exemplified by the findings that more than half of the ClC family members are antiporters, and not channels as was previously thought, and that bestrophins, previously prime candidates for Ca 2+ -activated Cl − channels, have been supplanted by the newly discovered anoctamins and now hold a tenuous position in the Cl − channel world. Keywords channelopathies; ion transport; bestrophin; TMEM16; anoctamin; ClC A Short History of Chloride in Biological SystemsNot long ago, Cl − channels were the Rodney Dangerfield of the ion channel field. Rodney Dangerfield (1921Dangerfield ( -2004) was a comedian who became famous for his joke: "I get no respect. I played hide-and-seek, and they wouldn't even look for me." After a small flurry of work on Cl − channels in the 50's and 60's, interest in Cl − channels dwindled until the 1990's. In the first edition of the "bible" on ion channels published in 1984 (1), less than 3 pages were devoted to Cl − channels, because it was thought that Cl − was usually in electrochemical equilibrium across cell membranes. This made Cl − less interesting than other ions that exhibited the potential to do some work. This mis-impression occurred because many early studies on Cl − were performed on skeletal muscle and erythrocytes where resting Cl − permeability is very high so that even if there is active Cl − transport present, Cl − is in electrochemical equilibrium. §Corresponding author: H. Criss Hartzell, Department of Cell Biology, 615 Michael St., 535 Whitehead Building, Emory, University School of Medicine, Atlanta, GA 30322, criss.hartzell@emory.edu, NIH Public Access Author ManuscriptAnnu Rev Physiol. Author manuscript; available in PMC 2011 March 17. Published in final edited form as:Annu Rev Physiol. 2010 March 17; 72: 95-121. doi:10.1146/annurev-physiol-021909-135811. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe demonstration that Cl − is actively transported in squid axons (2) and secreted (as HCl) by stomach (3) did not seem to attract much attention. Even the discovery that the inhibitory action of GABA was caused by an increased Cl − conductance did little to dispel the idea that Cl − could be out of electrochemical equilibrium. Because the reversal potentials of GABA-induced i.p.s.p.'s were very close to the resting potential, it was reasonably concluded that "normally Cl − ions are in electro-chemical equilibrium across the membrane" (4).Into the 1990's, the position of Cl − channels in cell...

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“…It has been proposed that a conserved Glutamate residue next to Glu in , serves as the intracellular H + acceptor in CLC channels [75-76]. When this residue, E291 in CLC-1, is mutated to Aspartate or Glutamine there is a drastic reduction in the open probability of the channel and a loss of sensitivity of the currents to the intracellular H + concentration [76]. While these results do not prove that E291 acts as a Glu in surrogate they are at least consistent with this hypothesis.…”

Section: A Degraded H+ Pathway Exists In the Clc Channelsmentioning

confidence: 99%

CLC channels and transporters: Proteins with borderline personalities

Accardi

Picollo

2010

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Controlled chloride movement across membranes is essential for a variety of physiological processes ranging from salt homeostasis in the kidneys to acidification of cellular compartments. The CLC family is formed by two, not so distinct, sub-classes of membrane transport proteins: Cl− channels and H+/Cl− exchangers. All CLC’s are homodimers with each monomer forming an individual Cl− permeation pathway which appears to be largely unaltered in the two CLC sub-classes. Key residues for ion binding and selectivity are also highly conserved. Most CLC’s have large cytosolic carboxy-terminal domains containing two cystathionine β-synthetase (CBS) domains. The C-termini are critical regulators of protein trafficking and directly modulate Cl− by binding intracellular ATP, H+ or oxidizing compounds. This review focuses on the recent mechanistic insights on the how the structural similarities between CLC channels and transporters translate in unexpected mechanistic analogies between these two sub-classes.

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Proton-coupled gating in chloride channels

Cited by 33 publications

References 43 publications

Molecular determinants of common gating of a ClC chloride channel

Molecular determinants of common gating of a ClC chloride channel

Chloride Channels: Often Enigmatic, Rarely Predictable

CLC channels and transporters: Proteins with borderline personalities

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