A rise in intracellular calcium is the predominant signal that leads to the activation of the contractile machinery in gastrointestinal smooth muscle. The primary sources of activating calcium are illustrated in Fig. 2. Voltage- and peptide-mediated release of intracellular calcium contribute to activation of some gastrointestinal smooth muscles. However, the primary source of activating calcium appears to be an influx of calcium across the plasma membrane. The degree of modulation of electrical activity by peptides varies depending upon the region of the gastrointestinal tract studied. Second messenger systems are undoubtly involved in the transduction pathway for receptor-mediated changes in ion channel activity in gastrointestinal smooth muscle. However, in comparison to other excitable cell types, little is known about the coupling mechanisms whereby peptide-receptor binding alters ion channel activity in gastrointestinal smooth muscle. This represents one of the challenging areas to be studied in the field of gastrointestinal smooth muscle. One disease in which a better appreciation of the regulation of ion channel activity could lead to therapeutic benefit is irritable bowel syndrome. A coupling of smooth muscle electrical activity to hypermotility in irritable bowel syndrome has been reported. CCK increases the level of spike activity which triggers hypermotility [40]. 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 of gastrointestinal smooth muscle ion channels expands, development of a gastrointestinal selective 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 spastic smooth muscle disorders.