Identification of sites responsible for the potentiating effect of niflumic acid on ClC-Ka kidney chloride channels.

ABSTRACT:

Background and purpose

ClC-K kidney Cl(-) channels are important for renal and inner ear transepithelial Cl(-) transport, and are potentially interesting pharmacological targets. They are modulated by niflumic acid (NFA), a non-steroidal anti-inflammatory drug, in a biphasic way: NFA activates ClC-Ka at low concentrations, but blocks the channel above approximately 1 mM. We attempted to identify the amino acids involved in the activation of ClC-Ka by NFA.

Experimental approach

We used site-directed mutagenesis and two-electrode voltage clamp analysis of wild-type and mutant channels expressed in Xenopus oocytes. Guided by the crystal structure of a bacterial CLC homolog, we screened 97 ClC-Ka mutations for alterations of NFA effects.

Key results

Mutations of five resi

SUBMITTER: Zifarelli G 

PROVIDER: S-EPMC2936838 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature