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1.A.13 The Epithelial Chloride Channel (E-ClC) Family

Mammals have multiple isoforms (at least 6 different gene products plus splice variants (Evans et al., 2004)) of epithelial chloride channel proteins. The first member of this family to be characterized was a respiratory epithelium, Ca2+-regulated, chloride channel protein isolated from bovine tracheal apical membranes. It was biochemically characterized as a 140 kDa complex. The purified complex when reconstituted in a planar lipid bilayer behaved as an anion-selective channel. It was regulated by Ca2+ via a calmodulin kinase II-dependent mechanism. When the cRNA was injected into Xenopus oocytes, an outward rectifying, DIDS-sensitive anion conductance was measured. A related gene, Lu-ECAM, was cloned from the bovine aortic endothelial cell line, BAEC. It is expressed in the lung and spleen but not in the trachea. Homologues are found in several mammals, and at least four paralogues (hCaCC-1-4) are present in humans, each with different tissue distributions.

The bovine EClC protein has 903 amino acids and four putative TMSs at residue positions 7-27, 331-351, 617-337 and 883-903. Distant (partial) homologues may be present in plants, ciliates and bacteria, Synechocystis (Sll0103; 420 aas) and E. coli (YfbK; 575 aas), so at least some domains within E-ClC family proteins have an ancient origin. E-ClC proteins show significant sequence similarity with CCA-α2δ family members (8.A.18).

Gibson et al. (2005) have shown that the human calcium-activated chloride channel, hCLCA1, is a secreted, non-integral membrane protein, and therefore suggest that this protein and its homologues are not ion channels at all. They also point out that the protein may not be sufficiently hydrophobic to insert into the membrane. Moreover, the proteins in subfamily 1.A.13.2 do not have α-TMSs, but hydrophilic domains in these proteins show sequence similarity to hydrophilic regions in proteins of family 8.A.18. The proteins without α-TMSs may not be channels. Thus, while some members of the E-ClC family appear to be able to form anion channels, others may not have this capacity.

The generalized reaction catalyzed by EClC family members is:

Cl- (in) Cl- (out)

References associated with 1.A.13 family:

Agnel, M., T. Vermat, and J. Culouscou. (1999). Identification of three novel members of the calcium-dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea. FEBS Lett. 455: 295-301. 10437792
Antonets, K.S., K.V. Volkov, A.L. Maltseva, L.M. Arshakian, A.P. Galkin, and A.A. Nizhnikov. (2016). Proteomic Analysis of Escherichia coli Protein Fractions Resistant to Solubilization by Ionic Detergents. Biochemistry (Mosc) 81: 34-46. 26885581
Barrett, K.E. and S.J. Keely. (2000). Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects. Annu. Rev. Physiol. 62: 535-572. 10845102
Bartenschlager, F., N. Klymiuk, C. Weise, B. Kuropka, A.D. Gruber, and L. Mundhenk. (2022). Evolutionarily conserved properties of CLCA proteins 1, 3 and 4, as revealed by phylogenetic and biochemical studies in avian homologues. PLoS One 17: e0266937. 35417490
Elble, R.C., G. Ji, K. Nehrke, J. DeBiasio, P.D. Kingsley, M.I. Kotlikoff, and B.U. Pauli. (2002). Molecular and functional characterization of a murine calcium-activated chloride channel expressed in smooth muscle. J. Biol. Chem. 277: 18586-18591. 11896056
Evans, S.R., W.B. Thoreson, and C.L. Beck. (2004). Molecular and functional analyses of two new calcium-activated chloride channel family members from mouse eye and intestine. J. Biol. Chem. 279: 41792-41800. 15284223
Fuller, C.M., I.I. Ismailov, D.A. Keeton, and D.J. Benos. (1994). Phosphorylation and activation of a bovine tracheal anion channel by Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 269: 26642-26650. 7929397
Gibson, A., A.P. Lewis, K. Affleck, A.J. Aitken, E. Meldrum, and N. Thompson. (2005). hCLCA1 and mCLCA3 are secreted non-integral membrane proteins and therefore are not ion channels. J. Biol. Chem. 280: 27205-27212. 15919655
Lee, R.M. and S.M. Jeong. (2016). [Identification of a Novel Calcium (Ca^(2+))-Activated Chloride Channel Accessory Gene in Xenopus laevis]. Mol Biol (Mosk) 50: 106-114. 27028816
Lee, R.M., R.H. Ryu, S.W. Jeong, S.J. Oh, H. Huang, J.S. Han, C.H. Lee, C.J. Lee, L.Y. Jan, and S.M. Jeong. (2011). Isolation and Expression Profile of the Ca-Activated Chloride Channel-like Membrane Protein 6 Gene in Xenopus laevis. Lab Anim Res 27: 109-116. 21826170
Ran, S. and D.J. Benos. (1992). Immunopurification and structural analysis of a putative epithelial Cl- channel protein isolated from bovine trachea. J. Biol. Chem. 267: 3618-3625. 1371273
Ran, S., C.M. Fuller, M. Pia Arrate, R. Latorre, and D.J. Benos. (1992). Functional reconstitution of a chloride channel protein from bovine trachea. J. Biol. Chem. 267: 20630-20637. 1383206
Sala-Rabanal, M., Z. Yurtsever, K.N. Berry, and T.J. Brett. (2015). Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases. Mediators Inflamm 2015: 497387. 26612971
Xin, W., J. Zhang, H. Zhang, X. Ma, Y. Zhang, Y. Li, and F. Wang. (2022). CLCA2 overexpression suppresses epithelial-to-mesenchymal transition in cervical cancer cells through inactivation of ERK/JNK/p38-MAPK signaling pathways. BMC Mol. Cell Biol. 23: 44. 36280802
Yoon, I.S., S.M. Jeong, S.N. Lee, J.H. Lee, J.H. Kim, M.K. Pyo, J.H. Lee, B.H. Lee, S.H. Choi, H. Rhim, H. Choe, and S.Y. Nah. (2006). Cloning and heterologous expression of a Ca2+-activated chloride channel isoform from rat brain. Biol Pharm Bull 29: 2168-2173. 17077509