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Mitochondrial matrix K+ flux independent of large-conductance Ca2+-activated K+ channel opening. Am J Physiol Cell Physiol 2010 Mar;298(3):C530-41

Date

01/08/2010

Pubmed ID

20053924

Pubmed Central ID

PMC2838564

DOI

10.1152/ajpcell.00468.2009

Scopus ID

2-s2.0-77749292115 (requires institutional sign-in at Scopus site)   51 Citations

Abstract

Large-conductance Ca(2+)-activated K(+) channels (BK(Ca)) in the inner mitochondrial membrane may play a role in protecting against cardiac ischemia-reperfusion injury. NS1619 (30 microM), an activator of BK(Ca) channels, was shown to increase respiration and to stimulate reactive oxygen species generation in isolated cardiac mitochondria energized with succinate. Here, we tested effects of NS1619 to alter matrix K(+), H(+), and swelling in mitochondria isolated from guinea pig hearts. We found that 30 microM NS1619 did not change matrix K(+), H(+), and swelling, but that 50 and 100 microM NS1619 caused a concentration-dependent increase in matrix K(+) influx (PBFI fluorescence) only when quinine was present to block K(+)/H(+) exchange (KHE); this was accompanied by increased mitochondrial matrix volume (light scattering). Matrix pH (BCECF fluorescence) was decreased slightly by 50 and 100 microM NS1619 but markedly more so when quinine was present. NS1619 (100 microM) caused a significant leak in lipid bilayers, and this was enhanced in the presence of quinine. The K(+) ionophore valinomycin (0.25 nM), which like NS1619 increased matrix volume and increased K(+) influx in the presence of quinine, caused matrix alkalinization followed by acidification when quinine was absent, and only alkalinization when quinine was present. If K(+) is exchanged instantly by H(+) through activated KHE, then matrix K(+) influx should stimulate H(+) influx through KHE and cause matrix acidification. Our results indicate that KHE is not activated immediately by NS1619-induced K(+) influx, that NS1619 induces matrix K(+) and H(+) influx through a nonspecific transport mechanism, and that enhancement with quinine is not due to the blocking of KHE, but to a nonspecific effect of quinine to enhance current leak by NS1619.

Author List

Aldakkak M, Stowe DF, Cheng Q, Kwok WM, Camara AK

Authors

Amadou K. Camara PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Wai-Meng Kwok PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Benzimidazoles
Dose-Response Relationship, Drug
Guinea Pigs
Hydrogen-Ion Concentration
Ion Channel Gating
Kinetics
Large-Conductance Calcium-Activated Potassium Channels
Light
Mitochondria, Heart
Mitochondrial Membranes
Mitochondrial Swelling
Potassium
Potassium-Hydrogen Antiporters
Quinine
Scattering, Radiation
Spectrophotometry
Valinomycin