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

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Zhang, Xun and Buckley, Charlotte and Lee, Matthew D. and Chalmers, Susan and Wilson, Calum and McCarron, John G. (2025) 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. The Journal of Physiology. ISSN 0022-3751 (https://doi.org/10.1113/JP288022)

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Abstract

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. image Key points: In smooth muscle Ca2⁺ entry via voltage‐dependent channels produces a uniform Ca2⁺ increase, enabling co‐ordinated contraction in each cell. Certain functions, however, require large, pulsatile Ca2⁺ changes rather than a uniform increase. Using advanced imaging in intact arteries, we discovered that voltage‐dependent Ca2⁺ entry triggers internal store Ca2⁺ release via IP₃ receptors, generating repetitive Ca2⁺ oscillations and waves. Mitochondria selectively modulate these signals by regulating only IP₃ receptor‐mediated release; neither mitochondrial location nor membrane potential is altered by either type of Ca2+ signal. These findings demonstrate how voltage‐dependent Ca2⁺ entry supports both co‐ordinated contraction and pulsatile Ca2⁺‐driven biological responses.

ORCID iDs

Zhang, Xun ORCID logoORCID: https://orcid.org/0000-0003-0790-4291, Buckley, Charlotte ORCID logoORCID: https://orcid.org/0000-0002-7961-4544, Lee, Matthew D. ORCID logoORCID: https://orcid.org/0000-0001-8265-382X, Chalmers, Susan ORCID logoORCID: https://orcid.org/0000-0002-8073-7576, Wilson, Calum ORCID logoORCID: https://orcid.org/0000-0003-2500-0632 and McCarron, John G. ORCID logoORCID: https://orcid.org/0000-0002-3302-3984;
CORE (COnnecting REpositories)