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State of ClCa phosphorylation affects the pharmacology of niflumic acid in rabbit pulmonary artery smooth muscle cells
Author(s) -
Wiwchar Michael,
Greenwood Ian A.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.579.8
Subject(s) - niflumic acid , chemistry , phosphorylation , calcineurin , stimulation , myocyte , phosphatase , dephosphorylation , biochemistry , medicine , endocrinology , biology , transplantation
Ca 2+ dependent Cl − currents (I ClCa ) are important modulators of membrane excitability in vascular smooth muscle cells. The underlying channel (Cl Ca ) appears to be negatively regulated by CaMKII‐induced phosphorylation, and up regulated by the phosphatase calcineurin. Niflumic acid (NFA), considered the most potent blocker of I ClCa in many cell types, both blocks and paradoxically enhances I ClCa in pulmonary artery (PA) myocytes. This study aimed to determine if the state of channel phosphorylation affects the pharmacology of NFA in dispersed rabbit PA myocytes. I ClCa was evoked by 500 nM free Ca 2+ . The ability of NFA to inhibit I ClCa was greatly reduced in conditions promoting phosphorylation. NFA also appeared to have a dual effect on I ClCa when applied at low concentrations (0.1‐10 μM), enhancing I ClCa in the presence of 5 mM ATP, while blocking I ClCa in cells dialyzed with10 µM KN‐93 (CaMKII inhibitor) and no ATP. Analysis of the voltage‐dependence of interaction of NFA with I ClCa showed that while the maximal level of block at positive potentials and stimulation at negative potentials were similar, dephosphorylation shifted the voltage at which conversion from block to stimulation occurs by more than ‐80 mV. These results show that the state of phosphorylation has a profound influence on the interaction of NFA with Cl Ca channels, which may explain the wide range of sensitivities to NFA reported in many studies.