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

Abstract

1 Pacemaker cells, known as interstitial cells of Cajal (ICC), generate electrical rhythmicity in the gastrointestinal tract. Pacemaker currents in ICC result from the activation of a voltage-independent, non-selective cation 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 metabolic activity 1y1yand1 Ca²⁺ release from intracellular stores. We tested the hypothesis that mitochondrial Ca²⁺ handling may underlie the dependence of gastrointestinal pacemaking on oxidative metabolism. 3 Pacemaker currents occurred spontaneously in cultured ICC and were associated with mitochondrial Ca²⁺ transients. 4 Inhibition of the electrochemical gradient across the inner mitochondrial membrane blocked Ca²⁺ uptake and pacemaker currents in cultured ICC and blocked slow wave activity in intact gastrointestinal muscles from mouse, dog and guinea-pig. 5 Pacemaker currents and rhythmic mitochondrial Ca²⁺ uptake in ICC were also blocked by inhibitors of IP₃-dependent release of Ca²⁺ from the endoplasmic 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 gastrointestinal tract.