Pacemaking in interstitial cells of Cajal depends upon calcium handling byendoplasmic reticulum and mitochondria

1. Pacemaker cells, known as interstitial cells of Cajal (ICC), generate el ectrical rhythmicity in the gastrointestinal tract. Pacemaker currents in I CC result from the activation of a voltage-independent, non-selective catio n conductance, but the timing mechanism responsible for periodic activation of the pacemaker current is unknown. 2. Previous studies suggest that pacemaking in ICC is dependent upon metabo lic activity and Ca2+ release from intracellular stores. We tested the hypo thesis that mitochondrial Ca2+ handling may underlie the dependence of gast rointestinal pacemaking on oxidative metabolism. 3. Pacemaker currents occurred spontaneously in cultured ICC and were assoc iated with mitochondrial Ca2+ transients. 4. Inhibition of the electrochemical gradient across the inner mitochondria l membrane blocked Ca2+ uptake and pacemaker currents in cultured ICC and b locked slow wave activity in intact gastrointestinal muscles from mouse, do g and guinea-pig. 5. Pacemaker currents and rhythmic mitochondrial Ca2+ uptake in ICC were al so blocked by inhibitors of IP3-dependent release of Ca2+ from the endoplas mic reticulum and by inhibitors of endoplasmic reticulum Ca2+ reuptake. 6. Our data suggest that integrated Ca2+ handling by endoplasmic reticulum and mitochondria is a prerequisite of electrical pacemaking in the gastroin testinal tract.