Clotrimazole-sensitive K⁺ currents regulate pacemaker activity in interstitial cells of Cajal

Abstract

Interstitial cells of Cajal (ICC) are pacemaker cells for gut peristaltic motor activity. Compared with cardiac pacemaker cells, little is known about mechanisms that regulate ICC excitability. The objective of the present study was to investigate a potential role for clotrimazole (CTL)-sensitive K currents (I(CTL)) in the regulation of ICC excitability and pacemaker activity. ICC were studied in situ and in short-term culture by using the whole cell patch-clamp configuration. In situ, ICC exhibited spontaneous transient inward currents followed by transient outward currents. CTL blocked outward currents, thereby increasing the net inward currents, and depolarized ICC, thereby establishing CTL-sensitive channels as regulators of ICC pacemaker activity. In short-term culture, a I(CTL) was identified that showed increased conductance when depolarized from the resting membrane potential to 0 mV and subsequent inward rectification at further depolarized potentials. The I(CTL) markedly increased with increasing intracellular calcium and was insensitive to the ether-à-go-go-related K channel blocker E-4031 and the large-conductance calcium-activated K channel blocker iberiotoxin. I(CTL) contributed 3-9 nS to the whole cell conductance at 0 mV membrane potential under physiological conditions; it was fast activating (tau = 88 ms), showed little time-dependent inactivation, and exhibited a deactivation time constant of 38 ms. The nitric oxide donor sodium nitroprusside (SNP) increased I(CTL). Single-channel activity, activated by calcium and SNP, was inhibited by CTL, with a single-channel conductance of approximately 38 pS. In summary, ICC generate a I(CTL) on depolarization through an intermediate-conductance calcium-activated K channel that regulates pacemaker activity and ICC excitability.

Transient outward potassium current in ICC

“…We found that the background current was carried by potassium and was of the "transient outward" type as characterized in cardiac cells (7). This furthers our previous study that was the first to record single potassium channels in ICC (36).…”

Multiple Neural Oscillators and Muscle Feedback Are Required for the Intestinal Fed State Motor Program

“…Activation of I K channels in enterocytes stimulates fluid secretion [44], and this could have an indirect effect on segmentation. Further, clotrimazole-sensitive potassium currents have been seen in ICC in mice [45]. Even though there is little slow-wave activity in the guinea-pig, if the I K channels blockers were acting on ICCs, they would be expected to influence the properties of isolated bursts, rather than the contractile episodes, because of the time course of potassium currents in these cells [46].…”

Modulation of Pacemaker Potentials in Murine Small Intestinal Interstitial Cells of Cajal by Gamisoyo-San, a Traditional Chinese Herbal Medicine

“…Additional studies are required to identify the ion channels involved, specifically K + channels that may be involved in the GSS-induced pacemaker potential depolarizations. There are many K + channels that possibly regulate ICC or GI motility, such as voltage-dependent K + channels (Kv channels) [42], Na + -K + -Cl – cotransporters [43], ATP-sensitive K + channels [44], voltage-gated Kv11.1 (hERG) channels [45], K V 7.5 channels [46], transient outward K + channels [47], Ca 2+ -activated K + channels [48], E-4031-sensitive K + channels [49], 4-AP-sensitive K + channels [50], and clotrimazole-sensitive K + channels [51]. GSS may have an effect on K + channels in ICCs and the possible effect of this on the pacemaker potential depolarization requires investigation.…”