Interstitial cells of Cajal (ICCs) are a fundamental component of the pacemaker apparatus of the gastrointestinal (GI) tract. They have special properties that make them unique in their ability to generate and propagate slow waves in gastrointestinal smooth muscle. The pacemaker current that generates slow waves is initially due to a voltage-independent, Ca(2+)-inhibited, non-selective cationic conductance in ICC. The classical transient receptor potential (TRPC) channel 4 was suggested as a molecular candidate for the nonselective cation channel (NSCC) responsible for the pacemaker activity. We have shown that TRPC4-/- mice display normal slow waves and suggest that TRPC4 might be an essential component of the NSCC activated by muscarinic stimulation. Finally, we suggest that TRPM7 is the molecular candidate for the NSCC responsible for pacemaker activity in ICCs on the basis of electrophysiological, molecular biological, and immunohistochemical experiments.