Genetic evidence for functional role of ryanodine receptor 1 in pulmonary artery smooth muscle cells |
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Authors: | Xiao-Qiang Li Yun-Min Zheng Rakesh Rathore Jianjie Ma Hiroshi Takeshima Yong-Xiao Wang |
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Institution: | (1) Center for Cardiovascular Sciences (MC-8), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA;(2) Department of Physiology and Biophysics, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA;(3) Department of Biological Chemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501, Japan |
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Abstract: | Ryanodine receptor 1 (RyR1) is well-known to be expressed in systemic and pulmonary vascular smooth muscle cells (SMCs); however,
its functional roles remain largely unknown. In the present study, we attempted to determine the potential importance of RyR1
in membrane depolarization-, neurotransmitter-, and hypoxia-induced Ca2+ release and contraction in pulmonary artery SMCs (PASMCs) using RyR1 homozygous and heterozygous gene deletion (RyR1−/− and RyR1+/−) mice. Our results indicate that spontaneous local Ca2+ release and caffeine-induced global Ca2+ release are significantly reduced in embryonic RyR1−/− and adult RyR+/− cells. An increase in Ca2+]i following membrane depolarization with high K+ is markedly attenuated in RyR1−/− and RyR1+/− PASMCs in normal Ca2+ or Ca2+-free extracellular solution. Similarly, muscle contraction evoked by membrane depolarization is reduced in RyR1+/− pulmonary arteries in the presence or absence of extracellular Ca2+. Neurotransmitter receptor agonists and inositol 1,4,5-triphosphate elicit a much smaller increase in Ca2+]i in both RyR1−/− and RyR1+/− cells. We have also found that neurotransmitter-evoked muscle contraction is significantly inhibited in RyR1+/− pulmonary arteries. Hypoxia-induced increase in Ca2+]i and contraction are largely blocked in RyR1−/− and/or RyR1+/− PASMCs. Collectively, our findings provide genetic evidence for the functional importance of RyR1 in spontaneous local Ca2+ release, and membrane depolarization-, neurotransmitter-, as well as hypoxia-induced global Ca2+ release and attendant contraction in PASMCs. |
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Keywords: | Ryanodine receptor Calcium release Membrane depolarization Hypoxia Pulmonary artery smooth muscle cell |
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