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Inhibition of vascular calcium‐gated chloride currents by blockers of K Ca 1.1, but not by modulators of K Ca 2.1 or K Ca 2.3 channels
Author(s) -
Sones WR,
Leblanc N,
Greenwood IA
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00332.x
Subject(s) - niflumic acid , chemistry , iberiotoxin , chloride channel , calcium , patch clamp , biophysics , conductance , biochemistry , receptor , biology , mathematics , organic chemistry , combinatorics
Background and purpose: Recent pharmacological studies have proposed there is a high degree of similarity between calcium‐activated Cl ‐ channels (CaCCs) and large conductance, calcium‐gated K + channels (K Ca 1.1). The goal of the present study was to ascertain whether blockers of K Ca 1.1 inhibited calcium‐activated Cl ‐ currents (I ClCa ) and if the pharmacological overlap between K Ca 1.1 and CaCCs extends to intermediate and small conductance, calcium‐activated K + channels. Experimental approaches: Whole‐cell Cl ‐ and K + currents were recorded from murine portal vein myocytes using the whole‐cell variant of the patch clamp technique. CaCC currents were evoked by pipette solutions containing 500 nM free [Ca 2+ ]. Key results: The selective K Ca 1.1 blocker paxilline (1 µM) inhibited I ClCa by ∼90%, whereas penitrem A (1 µM) and iberiotoxin (100 and 300 nM) reduced the amplitude of I ClCa by ∼20%, as well as slowing channel deactivation. Paxilline also abolished the stimulatory effect of niflumic acid on the CaCC. In contrast, an antibody against the Ca 2+ ‐binding domain of murine K Ca 1.1 had no effect on I ClCa while inhibiting spontaneous K Ca 1.1 currents. Structurally different modulators of small and intermediate conductance calcium‐activated K + channels (K Ca 2.1 and K Ca 2.3), namely 1‐EBIO, (100 µM); NS309, (1 µM); TRAM‐34, (10 µM); UCL 1684, (1 µM) had no effect on I ClCa . Conclusions and implications: These data show that the selective K Ca 1.1 blockers also reduce I ClCa considerably. However, the pharmacological overlap that exists between CaCCs and K Ca 1.1 does not extend to the calcium‐binding domain or to other calcium‐gated K + channels.