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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 8, 2007; DOI: 10.1124/jpet.106.118786

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Received for publication December 19, 2006.
Revised March 5, 2007.
Accepted for publication March 5, 2007.

Stimulation of Ca2+-Gated Cl- Currents by the Calcium-Dependent K+ Channel Modulators NS1619 and Isopimaric Acid

Sohag N Saleh 1, Jeff E Angermann 2, William R Sones 1, Normand Leblanc 2, Iain Greenwood 3*

1 St George's, University of London 2 University of Nevada Reno 3 St George's Univeristy of London

* Address correspondence to: E-mail: i.greenwood{at}sgul.ac.uk

Abstract

As chloride (Cl-) channel blockers such as niflumic acid enhance large conductance Ca2+-activated potassium channels (BKCa) the aim of this study was to determine if there is a reciprocal modification of Ca2+-activated chloride Cl- currents (IClCa) by two selective activators of BKCa. Single smooth muscle cells were isolated by enzymatic digestion from murine portal vein and rabbit pulmonary artery. The BKCa activators NS1619 and isopimaric acid (IpA) augmented macroscopic IClCa elicited by pipette solutions containing [Ca2+]i 100 nM without any alteration in current kinetics. Enhanced currents recorded in the presence of NS1619 or IpA reversed at the theoretical Cl- equilibrium potential, which was shifted by ~ -40 mV upon replacement of the external anion with the more permeable thiocyanate anion. NS1619 exerted its action by increasing the sensitivity of ClCa channels to Ca2+ (~ 100 nM at +60 mV) and by inducing a leftward shift in their voltage-dependence (~ 80 mV with 1 µM Ca2+). Single channel experiments revealed that NS1619 increased the open probability (NP0) of small conductance (1.8 - 3.1 pS) ClCa channels without any alteration in their unitary amplitude or number of observable unitary levels of activity. These data, in addition to the established stimulatory effects of NFA on BKCa, show that there is similarity in the pharmacology of calcium-activated chloride and potassium channels. Whilst non-specific interactions are possible, one alternative hypothesis is that the channel underlying vascular IClCa may share some structural similarity to the BKCa channel or that the latter K+ channel physically interacts with neighbouring ClCa channels.


Key words: Isopimaric acid, NS1619, Niflumic acid, calcium-activated chloride current, calcium-activated potassium channel, smooth muscle




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