Effects of Transient Receptor Potential Channel Blockers on Pacemaker Activity in Interstitial Cells of Cajal from Mouse Small Intestine

Abstract

The interstitial cells of Cajal (ICCs) are pacemakers in the gastrointestinal tract and transient receptor potential melastatin type 7 (TRPM7) is a candidate for pacemaker channels. The effect of the 5-lipoxygenase (5-LOX) inhibitors NDGA, AA861, MK886 and zileuton on pacemaking activity of ICCs was examined using the whole cell patch clamp technique. NDGA and AA861 decreased the amplitude of pacemaker potentials in ICC clusters, but the resting membrane potentials displayed little change, respectively. Also, perfusing NDGA and AA861 into the bath reduced both inward current and outward current in TRPM7-like current in single ICC, respectively. But, they had no effects on Ca 2+ activated Cl -currents. The 5-LOX inhibitors MK886 and zileuton were, however, ineffective in pacemaker potentials in ICC clusters and in TRPM7-like current in single ICC, respectively. A specific TRPC3 inhibitor, pyrazole compound (Pyr3), and a specific TRPM4 inhibitor, 9-phenanthrol, had no effects in pacemaker potentials in ICC clusters and in TRPM7-like current in single ICC. These results suggest that, among the tested 5-LOX inhibitors, NDGA and AA861 modulate the pacemaker activities of the ICCs, and that the TRPM7 channel can affect intestinal motility.

Involvement of Na+-leak Channel in Substance P-induced Depolarization of Pacemaking Activity in Interstitial Cells of Cajal

“…NDGA and AA861 decreased the amplitude of pacemaker potentials in ICC clusters, but the resting membrane potentials displayed little change. Also, perfusing NDGA and AA861 into the bath reduced both inward current and outward current in TRPM7-like current in single ICC [44]. But, they had no effects on the overexpressed tmen16a, Ca…”

“…-activated Cl -currents in HEK 293 cells [44]. Therefore, the nature of molecular candidates involved in the pacemaing activity in ICCs needs to be further investigated.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…During early embryogenesis, TRPM7 is critical for heart development (myocardial proliferation), although this mechanism seems to be dispensable after birth (Sah et al, 2013). In adult tissues, TRPM7 may play a role as a pacemaker channel in Cajal cells and thus affect intestinal motility (Kim et al, 2011a). The channel is also present in human atrial myocytes, where its expression is upregulated during atrial fibrillation (Zhang et al, 2012c).…”

Novel role for the transient potential receptor melastatin 4 channel in guinea pig detrusor smooth muscle physiology

“…In freshly isolated cerebral artery myocytes, 9-phenanthrol (30 M) did not alter the activity of the canonical (C) TRP channels TRPC3 and TRPC6, voltage-gated K ϩ (K v ), large conductance Ca 2ϩ -activated K ϩ (BK), inwardly rectifying K ϩ (K ir ), and VDCC (17). 9-Phenanthrol was also shown to have no effect on TRPM7 currents in mouse interstitial cells of Cajal (26). Furthermore, 9-phenanthrol has been shown to block TRPM4 currents in cerebral blood vessels and evoke substantial hyperpolarization of vascular smooth muscle cell membrane potential and dilation of arteries with myogenic tone (17).…”