Mitochondria regulate inositol triphosphate‐mediated Ca 2+ release triggered by voltage‐dependent Ca 2+ entry in resistance arteries: Ca2+ entry activates IP3 receptors in smooth muscle

An increase in cytoplasmic Ca2+ concentration activates multiple cellular activities, including cell division, metabolism, growth, contraction and death. In smooth muscle Ca2+ entry via voltage-dependent Ca2+ channels leads to a relatively uniform increase in cytoplasmic Ca2+ levels that facilitates co-ordinated contraction throughout the cell. However certain functions triggered by voltage-dependent Ca2+ channels require periodic, pulsatile Ca2+ changes. The mechanism by which Ca2+ entry through voltage-dependent channels supports both co-ordinated contraction and distinct cellular responses driven by pulsatile Ca2+ changes is unclear. Here in intact resistance arteries we show that Ca2+ entry via voltage-dependent Ca2+ channels evokes Ca2+ release via inositol triphosphate receptors (IP3Rs), generating repetitive Ca2+ oscillations and waves. We also show that mitochondria play a vital role in regulating Ca2+ signals evoked by voltage-dependent Ca2+ entry by selectively modulating Ca2+ release via IP3Rs. Depolarizing the mitochondrial membrane inhibits Ca2+ release from internal stores, reducing the overall signal-generated Ca2+ influx without altering the signal resulting from voltage-dependent Ca2+ entry. Notably neither Ca2+ entry via voltage-dependent Ca2+ channels nor Ca2+ release via IP3Rs alters mitochondrial location or mitochondrial membrane potential in intact smooth muscle cells. Collectively these results demonstrate that activation of voltage-dependent Ca2+ channels drives Ca2+ entry, which subsequently triggers Ca2+ release from the internal store in smooth muscle cells. Mitochondria selectively regulate this process by modulating IP3R-mediated amplification of Ca2+ signals, ensuring that different cellular responses are precisely controlled.