A human intermediate conductance calcium-activated potassium channel

Abstract

An intermediate conductance calciumactivated potassium channel, hIK1, was cloned from human pancreas. The predicted amino acid sequence is related to, but distinct from, the small conductance calcium-activated potassium channel subfamily, which is Ϸ50% conserved. hIK1 mRNA was detected in peripheral tissues but not in brain. Expression of hIK1 in Xenopus oocytes gave rise to inwardly rectifying potassium currents, which were activated by submicromolar concentrations of intracellular calcium (K 0.5 ‫؍‬ 0.3 M). Although the K 0.5 for calcium was similar to that of small conductance calcium-activated potassium channels, the slope factor derived from the Hill equation was significantly reduced (1.7 vs. 3.5). Single-channel current amplitudes ref lected the macroscopic inward rectification and revealed a conductance level of 39 pS in the inward direction. hIK1 currents were reversibly blocked by charybdotoxin (K i ‫؍‬ 2.5 nM) and clotrimazole (K i ‫؍‬ 24.8 nM) but were minimally affected by apamin (100 nM), iberiotoxin (50 nM), or ketoconazole (10 M). These biophysical and pharmacological properties are consistent with native intermediate conductance calcium-activated potassium channels, including the erythrocyte Gardos channel.

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

“…Although others have raised uncertainty about the presence of IK channels in DRG neurons [42,44,77,78], our identification of a clotrimazole-sensitive current suggests that a component of I K(Ca) in these neurons is IK. Other prior observations also support our finding of BK currents in DRG somata [83,102].…”

The antifungal antibiotic clotrimazole alters calcium homeostasis of leukemic lymphoblasts and induces apoptosis

“…7,[10][11][12][13][14][15] To determine whether clotrimazole affected Ca 2+ homeostasis in ALL cells, we measured changes in cytosolic Ca 2+ concentration in the leukemic cell line 380. Exposure to 10 m clotrimazole induced a detectable increase in cytosolic Ca 2+ concentration, as shown by an increased Indo-1 fluorescence signal ratio; this increase became clearly evident after exposure to 50 m of the drug (Figure 7).…”

“…[3][4][5] Normally, this release induces the opening of plasma membrane Ca 2+ channels and activates the intermediate-conductance Ca 2+ -activated K + (IK) channel, allowing Ca 2+ influx from the extracellular space. [3][4][5][6][7][8][9] Clotrimazole disrupts cellular Ca 2+ homeostasis by releasing Ca 2+ from intracellular stores while inhibiting Ca 2+ influx and blocking IK channels. 7,[10][11][12][13][14][15] It is being evaluated clinically for the treatment of IK channel-driven erythrocyte dehydration in sickle cell dis- ease 16,17 and the treatment of secretory diarrheas that involve chloride secretion through IK channels.…”

Maternal Diabetes Increases Small Conductance Ca2+-Activated K+(SK) Currents That Alter Action Potential Properties and Excitability of Cardiac Motoneurons in the Nucleus Ambiguus

“…Activation of these channels generates currents that contribute to AP repolarization and the afterhyperpolarization (AHP) that follows them (Lancaster and Pennefather 1987;Sah and McLachlan 1992;Storm 1987). There are three major types of Ca 2ϩ -activated K ϩ channels: 1) large conductance (BK) voltagesensitive channels that are potently blocked by the scorpion venom toxin charybdotoxin (ChTX) and selectively blocked by paxilline (Sanchez and McManus 1996;Strøbaek et al 1996); 2) intermediate conductance (IK) channels that are potently blocked by ChTX and the antifungal imidazole compound clotrimazole (CTL) (Ishii et al 1997;Logsdon et al 1997); and 3) small conductance (SK) voltage-insensitive channels that are selectively blocked by the bee toxin apamin (Castle et al 1989). BK currents mainly contribute to AP repolarization and the fast AHP (fAHP, a few milliseconds) (Faber and Sah 2007) that immediately follows it (Lancaster and Adams 1986;Lancaster and Nicoll 1987;Sah and McLachlan 1992;Storm 1987), whereas activation of SK currents largely generates medium AHP (mAHP; tens to several hundreds milliseconds), which significantly mediates firing frequency and patterns (Sah 1996).…”