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NEUROREGULATION AND MOTILITY

Effects of the gap junction blocker glycyrrhetinic acid on gastrointestinal smooth muscle cells

Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada

Submitted 27 August 2004 ; accepted in final form 1 November 2004

In the tunica muscularis of the gastrointestinal (GI) tract, gap junctions form low-resistance pathways between pacemaker cells known as interstitial cells of Cajal (ICCs) and between ICC and smooth muscle cells. Coupling via these junctions facilitates electrical slow-wave propagation and responses of smooth muscle to enteric motor nerves. Glycyrrhetinic acid (GA) has been shown to uncouple gap junctions, but previous studies have shown apparent nonspecific effects of GA in a variety of tissues. We tested the effects of GA using isometric force measurements, intracellular microelectrode recordings, the patch-clamp technique, and the spread of Lucifer yellow within cultured ICC networks. In murine small intestinal muscles, -GA (10 µM) decreased phasic contractions and depolarized resting membrane potential. Preincubation of GA inhibited the spread of Lucifer yellow, increased input resistance, and decreased cell capacitance in ICC networks, suggesting that GA uncoupled ICCs. In patch-clamp experiments of isolated jejunal myocytes, GA significantly decreased L-type Ca²⁺ current in a dose-dependent manner without affecting the voltage dependence of this current. The IC₅₀ for Ca²⁺ currents was 1.9 µM, which is lower than the concentrations used to block gap junctions. GA also significantly increased large-conductance Ca²⁺-activated K⁺ currents but decreased net delayed rectifier K⁺ currents, including 4-aminopyridine and tetraethylammonium-resistant currents. In conclusion, the reduction of phasic contractile activity of GI muscles by GA is likely a consequence of its inhibitory effects on gap junctions and voltage-dependent Ca²⁺ currents. Membrane depolarization may be a consequence of uncoupling effects of GA on gap junctions between ICCs and smooth muscles and inhibition of K⁺ conductances in smooth muscle cells.

gastrointestinal motility; calcium ion currents; potassium ion currents; interstitial cells of Cajal; smooth muscle

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