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XB-ART-49319
Biochim Biophys Acta 2014 Nov 01;183811:2745-56. doi: 10.1016/j.bbamem.2014.07.021.
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I-J loop involvement in the pharmacological profile of CLC-K channels expressed in Xenopus oocytes.

Gradogna A , Imbrici P , Zifarelli G , Liantonio A , Camerino DC , Pusch M .


Abstract
CLC-K chloride channels and their subunit, barttin, are crucial for renal NaCl reabsorption and for inner ear endolymph production. Mutations in CLC-Kb and barttin cause Bartter syndrome. Here, we identified two adjacent residues, F256 and N257, that when mutated hugely alter in Xenopus oocytes CLC-Ka's biphasic response to niflumic acid, a drug belonging to the fenamate class, with F256A being potentiated 37-fold and N257A being potently blocked with a KD~1μM. These residues are localized in the same extracellular I-J loop which harbors a regulatory Ca(2+) binding site. This loop thus can represent an ideal and CLC-K specific target for extracellular ligands able to modulate channel activity. Furthermore, we demonstrated the involvement of the barttin subunit in the NFA potentiation. Indeed the F256A mutation confers onto CLC-K1 a transient potentiation induced by NFA which is found only when CLC-K1/F256A is co-expressed with barttin. Thus, in addition to the role of barttin in targeting and gating, the subunit participates in the pharmacological modulation of CLC-K channels and thus represents a further target for potential drugs.

PubMed ID: 25073071
PMC ID: PMC4331650
Article link: Biochim Biophys Acta
Grant support: [+]

Species referenced: Xenopus
Genes referenced: bsnd clcnkb cpa1


Article Images: [+] show captions
References [+] :
Accardi, Conformational changes in the pore of CLC-0. 2003, Pubmed, Xenbase