Inhibition of vascular calcium-gated chloride currents by blockers of KCa1.1, but not by modulators of KCa2.1 or KCa2.3 channels

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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 (KCa1.1). The goal of the present study was to ascertain whether blockers of KCa1.1 inhibited calcium-activated Cl currents (IClCa) and if the pharmacological overlap between KCa1.1 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 [Ca2+].Key results:The selective KCa1.1 blocker paxilline (1 μM) inhibited IClCa by ˜90%, whereas penitrem A (1 μM) and iberiotoxin (100 and 300 nM) reduced the amplitude of IClCa 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 Ca2+-binding domain of murine KCa1.1 had no effect on IClCa while inhibiting spontaneous KCa1.1 currents. Structurally different modulators of small and intermediate conductance calcium-activated K+ channels (KCa2.1 and KCa2.3), namely 1-EBIO, (100 μM); NS309, (1 μM); TRAM-34, (10 μM); UCL 1684, (1 μM) had no effect on IClCa.Conclusions and implications:These data show that the selective KCa1.1 blockers also reduce IClCa considerably. However, the pharmacological overlap that exists between CaCCs and KCa1.1 does not extend to the calcium-binding domain or to other calcium-gated K+ channels.

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