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Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA

Mitochondria sequester and release calcium (Ca²⁺) and regulate intracellular Ca²⁺ concentration ([Ca²⁺]_i) in eukaryotic cells. However, the regulation of different Ca²⁺ signalling modalities by mitochondria in smooth muscle cells is poorly understood. Here, we investigated the regulation of Ca²⁺ sparks, Ca²⁺ waves and global [Ca²⁺]_i by mitochondria in cerebral artery smooth muscle cells. CCCP (a protonophore; 1 µM) and rotenone (an electron transport chain complex I inhibitor; 10 µM) depolarized mitochondria, reduced Ca²⁺ spark and wave frequency, and elevated global [Ca²⁺]_i in smooth muscle cells of intact arteries. In voltage-clamped (–40 mV) cells, mitochondrial depolarization elevated global [Ca²⁺]_i, reduced Ca²⁺ spark amplitude, spatial spread and the effective coupling of sparks to large-conductance Ca²⁺-activated potassium (K_Ca) channels, and decreased transient K_Ca current frequency and amplitude. Inhibition of Ca²⁺ sparks and transient K_Ca currents by mitochondrial depolarization could not be explained by a decrease in intracellular ATP or a reduction in sarcoplasmic reticulum Ca²⁺ load, and occurred in the presence of diltiazem, a voltage-dependent Ca²⁺ channel blocker. Ru360 (10 µM), a mitochondrial Ca²⁺ uptake blocker, and lonidamine (100 µM), a permeability transition pore (PTP) opener, inhibited transient K_Ca currents similarly to mitochondrial depolarization. In contrast, CGP37157(10 µM), a mitochondrial Na⁺–Ca²⁺ exchange blocker, activated these events. The PTP blockers bongkrekic acid and cyclosporin A both reduced inhibition of transient K_Ca currents by mitochondrial depolarization. These results indicate that mitochondrial depolarization leads to a voltage-independent elevation in global [Ca²⁺]_i and Ca²⁺ spark and transient K_Ca current inhibition. Data also suggest that mitochondrial depolarization inhibits Ca²⁺ sparks and transient K_Ca currents via PTP opening and a decrease in intramitochondrial [Ca²⁺].

(Received 12 December 2003; accepted after revision 5 February 2004; first published online 6 February 2004)
Corresponding author J. H. Jaggar: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.  Email: jjaggar{at}physio1.utmem.edu

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