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
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





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Item type: Article ID code: 92401 Dates: DateEvent5 May 2025Published5 May 2025Published Online19 March 2025AcceptedSubjects: Medicine > Pharmacy and materia medica Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 20 Mar 2025 11:16 Last modified: 15 May 2025 09:19 Related URLs: URI: https://strathprints.strath.ac.uk/id/eprint/92401