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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Caffeine inhibits nonselective cationic currents in interstitial cells of Cajal from the murine jejunum

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

Submitted 6 April 2009 ; accepted in final form 21 July 2009

Interstitial cells of Cajal (ICC) discharge unitary potentials in gastrointestinal muscles that constitute the basis for pacemaker activity. Caffeine has been used to block unitary potentials, but the ionic conductance responsible for unitary potentials is controversial. We investigated currents in cultured ICC from murine jejunum that may underlie unitary potentials and studied the effects of caffeine. Networks of ICC generated slow wave events under current clamp, and these events were blocked by caffeine in a concentration-dependent manner. Single ICC generated spontaneous transient inward currents (STICs) under voltage clamp at –60 mV and noisy voltage fluctuations in current clamp. STICs were unaffected when the equilibrium potential for Cl^– (E_Cl) was set to –60 mV (excluding Cl^– currents) and reversed at 0 mV, demonstrating that a nonselective cationic conductance, and not a Cl^– conductance, is responsible for STICs in ICC. Caffeine inhibited STICs in a concentration-dependent manner. Reduced intracellular Ca²⁺ and calmidazolium (CMZ; 1 µM) activated persistent inward, nonselective cation currents in ICC. Currents activated by CMZ and by dialysis of cells with 10 mM BAPTA were also inhibited by caffeine. Excised inside-out patches contained channels that exhibited spontaneous openings, and resulting currents reversed at 0 mV. Channel openings were increased by reducing Ca²⁺ concentration from 10^–6 M to 10^–8 M. CMZ (1 µM) also increased openings of nonselective cation channels. Spontaneous currents and channels activated by CMZ were inhibited by caffeine (5 mM). The findings demonstrate that the Ca²⁺-inhibited nonselective cation channels that generate STICs in ICC are blocked directly by caffeine. STICs are responsible for unitary potentials in intact muscles, and the block of these events by caffeine is consistent with the idea that a nonselective cation conductance underlies unitary potentials in ICC.

pacemaker; visceral smooth muscle; gastrointestinal motility; slow wave; electrical rhythmicity; spontaneous transient inward currents; nonselective cationic currents