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Am J Physiol Lung Cell Mol Physiol 296: L347-L360, 2009. First published December 19, 2008; doi:10.1152/ajplung.90341.2008
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Cellular localization of mitochondria contributes to K_v channel-mediated regulation of cellular excitability in pulmonary but not mesenteric circulation

¹Department of Pharmacy and Pharmacology, University of Bath, Bath; and ²Division of Basic Medical Sciences, Ion Channels and Cell Signalling Centre, St George's University of London, London, United Kingdom; and ³Laboratory of Molecular Pharmacology and Biophysics of Cell Signaling, Bogomoletz Institute of Physiology, Kiev, Ukraine

Submitted 11 June 2008 ; accepted in final form 16 December 2008

Mitochondria are proposed to be a major oxygen sensor in hypoxic pulmonary vasoconstriction (HPV), a unique response of the pulmonary circulation to low oxygen tension. Mitochondrial factors including reactive oxygen species, cytochrome c, ATP, and magnesium are potent modulators of voltage-gated K⁺ (K_v) channels in the plasmalemmal membrane of pulmonary arterial (PA) smooth muscle cells (PASMCs). Mitochondria have also been found close to the plasmalemmal membrane in rabbit main PA smooth muscle sections. Therefore, we hypothesized that differences in mitochondria localization in rat PASMCs and systemic mesenteric arterial smooth muscle cells (MASMCs) may contribute to the divergent oxygen sensitivity in the two different circulations. Cellular localization of mitochondria was compared with immunofluorescent labeling, and differences in functional coupling between mitochondria and K_v channels was evaluated with the patch-clamp technique and specific mitochondrial inhibitors antimycin A (acting at complex III of the mitochondrial electron transport chain) and oligomycin A (which inhibits the ATP synthase). It was found that mitochondria were located significantly closer to the plasmalemmal membrane in PASMCs compared with MASMCs. Consistent with these findings, the effects of the mitochondrial inhibitors on K_v current (I_Kv) were significantly more potent in PASMCs than in MASMCs. The cytoskeletal disruptor cytochalasin B (10 µM) also altered mitochondrial distribution in PASMCs and significantly attenuated the effect of antimycin A on the voltage-dependent parameters of I_Kv. These findings suggest a greater structural and functional coupling between mitochondria and K_v channels specifically in PASMCs, which could contribute to the regulation of PA excitability in HPV.

pulmonary artery; vascular smooth muscle cells; mesenteric artery; K⁺ channel activation; K⁺ channel inactivation; confocal imaging; patch-clamp technique