A rise in intracellular calcium is the predominant signal that leads to the activation of the contractile machinery ingastrointestinalsmooth muscle. The primary sources of activating calcium are illustrated in Fig. 2. Voltage- and peptide-mediated release of intracellular calcium contribute to activation of somegastrointestinalsmoothmuscles. However, the primary source of activating calcium appears to be an influx of calcium across the plasma membrane. The degree ofmodulationofelectricalactivitybypeptidesvaries depending upon the region of thegastrointestinaltract studied. Second messenger systems are undoubtly involved in the transduction pathway for receptor-mediated changes in ion channelactivityingastrointestinalsmooth muscle. However, in comparison to other excitable cell types, little is known about the coupling mechanisms whereby peptide-receptor binding alters ion channelactivityingastrointestinalsmooth muscle. This represents one of the challenging areas to be studied in the field ofgastrointestinalsmooth muscle. One disease in which a better appreciation of the regulation of ion channelactivitycould lead to therapeutic benefit is irritable bowel syndrome. A coupling ofsmooth muscleelectricalactivityto hypermotility in irritable bowel syndrome has been reported. CCK increases the level of spikeactivitywhich triggers hypermotility . It would follow that inhibition of calcium influx should reduce spiking and, therefore, hypermotility. In fact, the calcium channel blockers nifedipine and nicardipine have been shown to decrease colonic motility in irritable bowel syndrome patients [62-64]. As our understanding ofgastrointestinalsmooth muscleion channels expands, development of agastrointestinalselective calcium channel blocker may be possible. This class of agents would be effective in the treatment of irritable bowel syndrome and potentially other peptide-related spasticsmooth muscledisorders.