Chloride Channels: Often Enigmatic, Rarely Predictable

Abstract

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...

Anoctamin 6 Contributes to Cl− Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea

“…To date, 10 members of the ANO gene family have been identified in mammals (ANO1-10 or TMEM16a-h and j and k) and predicted to be transmembrane proteins containing eight membrane-spanning helices with the N and C termini located in the cytosol (12)(13)(14). Each member is predicted to have multiple isoforms being simultaneously expressed in a given cell (15). Apart from ANO1 and ANO2, ANO6 was also recently shown to be a Ca 2ϩ -activated Cl Ϫ channel with delayed Ca 2ϩ activation (16,17).…”

Preassociated apocalmodulin mediates Ca 2+ -dependent sensitization of activation and inactivation of TMEM16A/16B Ca 2+ -gated Cl − channels

“…There are two possible nonexclusive mechanisms: (i) direct Ca 2+ binding to the channel or (ii) Ca 2+ binding through a separate Ca 2+ -sensing protein. The TMEM16A sequence does not reveal any canonical Ca 2+ -binding EF hand motifs (14,16,17). A sequence in the first intracellular loop of TMEM16A resembling the "Ca 2+ bowl" in large conductance Ca 2+ -activated K + (BK) channels was disqualified by mutagenesis as the Ca 2+ sensor responsible for CDA of TMEM16A (28).…”

Anoctamin 1 (Tmem16A) Ca 2 + -activated chloride channel stoichiometrically interacts with an ezrin–radixin–moesin network

“…calcium | interactome | cross-linker | apical targeting C a 2+ -activated Cl − channels (CaCCs) play critical roles in epithelial secretion, sensory transduction and adaptation, regulation of smooth muscle contraction, control of neuronal and cardiac excitability, and nociception (1,2). In 2008, after many years of controversy about the molecular identity of CaCCs, Ano1 and Ano2 (also called Tmem16A and Tmem16B) of the Anoctamin superfamily were identified as essential subunits of CaCCs (3)(4)(5).…”