HYPOXIA AND CONSEQUENCES Hypoxia Selectively Inhibits KCNA5 Channels in Pulmonary Artery Smooth Muscle Cells Amy L. Firth, Oleksandr Platoshyn, Elena E. Brevnova, Elyssa D. Burg, Frank Powell, Gabriel H. Haddad, and Jason X.-J. Yuan Departments of Medicine and Pediatrics, University of California, San Diego, La Jolla, California, USA Acute hypoxia induces pulmonary vasoconstriction and chronic hypoxia causes pul- monary vascular remodeling characterized by significant vascular medial hypertrophy. Electromechanical and pharmacomechanical mechanisms are involved in regulating pulmonary vasomotor tone, while changes in cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ) are an important signal in regulating contraction and proliferation of pulmonary artery smooth muscle cells (PASMC). Hypoxia-induced increases in [Ca 2+ ] cyt are, in part, medi- ated by selective inhibition of voltage-gated K + (Kv) channels in PASMC. Kv1.5, encoded by the KCNA5 gene, is a Kv channel α subunit that forms functional homotetrameric and heterotetrameric Kv channels in PASMC. Activity of Kv channels contributes to the regulation of resting membrane potential. Overexpression of the human KCNA5 gene in rat PASMC and other cell types increases whole-cell Kv currents and causes membrane hyperpolarization. However, acute hypoxia only reduced Kv currents in KCNA5-transfected PASMC. These results provide compelling evidence that Kv1.5 is an important hypoxia-sensitive Kv channel in PASMC, contributing to regulation of membrane potential and intracellular Ca 2+ homeostasis during hypoxia. This hypoxia- sensitive mechanism essential for inhibiting Kv1.5 channel activity is exclusively present in PASMC. Key words: membrane potential; K + channels; pulmonary artery smooth muscle cells (PASMC); vascular smooth muscle; hypoxic pulmonary vasoconstriction (HPV) Introduction Vasoconstriction in response to alveolar hy- poxia is a unique physiological response ob- served in pulmonary arteries and arterioles. Such a response, known as hypoxic pulmonary vasoconstriction (HPV), is a critical mechanism that directs blood flow away from poorly ven- tilated regions in the lung to maintain an op- timal ventilation/perfusion ratio for the max- imal oxygenation of the venous blood in the pulmonary artery. An increase in cytosolic free Address for correspondence: Jason X.-J. Yuan, M.D., Ph.D., Depart- ment of Medicine, University of California, San Diego, 9200 Gilman Drive, La Jolla, CA 92093-0725, USA. Voice: 858-822-6534; fax: 858- 822-6531. xiyuan@ucsd.edu Ca 2+ concentration ([Ca 2+ ] cyt ) in pulmonary artery smooth muscle cells (PASMC) is a ma- jor trigger for pulmonary vasoconstriction. A rise in [Ca 2+ ] cyt also serves as an important stimulus for cell migration, proliferation, and gene expression. 1,2 Increased [Ca 2+ ] cyt (1) ac- tivates myosin light chain kinase, contracting PASMC 3 ; (2) enhances proliferation by stimu- lating entry of quiescent cells into the cell cy- cle by driving proliferating cells to mitosis and by activating cytoplasmic signal transduction proteins directly or indirectly involved in pro- motion of cell proliferation 1 ; and (3) activates Ca 2+ /calmodulin-dependent protein kinase II (CaM kinase II) required for PASMC migra- tion. 4 The inherent involvement of [Ca 2+ ] cyt in the development of HPV requires an extensive Hypoxia and Consequences: Ann. N.Y. Acad. Sci. 1177: 101–111 (2009). doi: 10.1111/j.1749-6632.2009.05040.x c  2009 New York Academy of Sciences. 101