Electric pacemaker activity drives peristaltic and segmental contractions in the gastrointestinal tract. Interstitial cells of Cajal (ICC) are responsible for spontaneous pacemaker activity. ICC remain rhythmic in culture and generate voltage-independent inward currents via a nonselective cation conductance. Ca(2+) release from endoplasmic reticulum and uptake by mitochondria initiates pacemaker currents. This novel mechanism provides the basis for electric rhythmicity in gastrointestinal muscles.