Mitochondrial modulation of Ca2+ sparks and transient KCa currents in smooth muscle cells of rat cerebral arteries

Serguei Y. Cheranov, Jonathan Jaggar

Research output: Contribution to journalArticle

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Abstract

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 (KCa) channels, and decreased transient KCa current frequency and amplitude. Inhibition of Ca2+ sparks and transient KCa 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 KCa 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 KCa 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 KCa current inhibition. Data also suggest that mitochondrial depolarization inhibits Ca2+ sparks and transient KCa currents via PTP opening and a decrease in intramitochondrial [Ca2+].

Original languageEnglish (US)
Pages (from-to)755-771
Number of pages17
JournalJournal of Physiology
Volume556
Issue number3
DOIs
StatePublished - May 1 2004

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Cerebral Arteries
Smooth Muscle Myocytes
Mitochondria
Permeability
Bongkrekic Acid
Carbonyl Cyanide m-Chlorophenyl Hydrazone
Electron Transport Complex I
Rotenone
Diltiazem
Potassium Channels
Sarcoplasmic Reticulum
Eukaryotic Cells
Cyclosporine
Arteries
Adenosine Triphosphate
Calcium

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

Mitochondrial modulation of Ca2+ sparks and transient KCa currents in smooth muscle cells of rat cerebral arteries. / Cheranov, Serguei Y.; Jaggar, Jonathan.

In: Journal of Physiology, Vol. 556, No. 3, 01.05.2004, p. 755-771.

Research output: Contribution to journalArticle

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