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Allosteric and state‐dependent interactions can explain the paradoxical block and stimulation of native and Tmem16a‐induced Ca2+‐activated Cl− currents by anthracene‐9‐carboxylic acid
Author(s) -
Thibeault Corey,
Wiwchar Michael,
Huebner Marissa,
Ayon Ramon J.,
Greenwood Iain A.,
Leblanc Normand
Publication year - 2011
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.25.1_supplement.1081.8
Subject(s) - allosteric regulation , anthracene , chemistry , stimulation , biophysics , block (permutation group theory) , stereochemistry , photochemistry , biochemistry , biology , neuroscience , enzyme , mathematics , geometry
Anthracene‐9‐Carboxylic Acid (A9C) is a Cl − channel blocker that paradoxically blocks and stimulates Ca 2+ ‐activated Cl − currents (I ClCa ) in vascular smooth muscle cells (Piper & Greenwood, Br J Pharmacol 138 : 31–38, 2003), and appears to produce a similar effect on I ClCa elicited by heterologous expression of Tmem16a (Davis et al., Am J Physiol Cell Physiol 299 : C948‐C959, 2010), a gene postulated to encode these channels. The purpose of this study was to evaluate whether we could create a computer model reproducing the effects of A9C on I ClCa . A model similar to that implemented by Kuruma & Hartzell ( J Gen Physiol 115 : 59–80, 2000) and Angermann et al. ( J Gen Physiol 128 : 73–87, 2006) simulated I ClCa , and involved 3 consecutive voltage‐independent Ca 2+ binding steps, each yielding channel opening, and 3 voltage‐dependent closure steps. Experimental data could be well reproduced by assuming the existence of two binding sites for A9C, one lying within the pore and conferring open state‐dependent block, and the other modulating gating by shifting the voltage‐dependence of the closure rate constants to more negative potentials. These results provide a mechanistic interpretation for the complex interaction of A9C with I ClCa that may pave the way for the development of pharmacological agents providing selective inhibition or stimulation of the channels for research and therapeutics purposes.