A central role for oxygen-sensitive K+ channels and mitochondria in the specialized oxygen-sensing system

Stephen L. Archer, Evangelos D. Michelakis, Bernard Thébaud, Sebastien Bonnet, Rohit Moudgil, Xi Chen Wu, E. Kenneth Weir

Research output: Chapter in Book/Report/Conference proceedingConference contribution

22 Scopus citations

Abstract

Mammals possess a specialized O2-sensing system (SOS), which compensates for encounters with hypoxia that occur during development, disease, and at altitude. Consisting of the resistance pulmonary arteries (PA), ductus arteriosus, carotid body, neuroepithelial body, systemic arteries, fetal adrenomedullary cell and fetoplacental arteries, the SOS optimizes O 2-uptake and delivery. Hypoxic pulmonary vasoconstriction (HPV), a vasomotor response of resistance PAs to alveolar hypoxia, optimizes ventilation/perfusion matching and systemic pO2. Though modulated by the endothelium, HPV's core mechanism resides in the smooth muscle cell (SMC). The Redox Theory proposes that HPV results from the coordinated action of a redox sensor (proximal mitochondrial electron transport chain) which generates a diffusible mediator (a reactive O2 species, ROS) that regulates effector proteins (voltage-gated Kv channels). Hypoxic withdrawal of ROS inhibits Kv1.5 and Kv2.1, depolarizes PASMCs, activates voltage-gated Ca2+ channels, increasing Ca2+ influx and causing vasoconstriction. Hypoxia's effect on ROS (decrease vs. increase) and the molecular origins of ROS (mitochondria vs. NADPH oxidase) remains controversial. Distal to this pathway, Rho kinase regulates the contractile apparatus' sensitivity to Ca2+. Also, a role for cADP ribose as a redox-regulated mediator of intracellular Ca2+ release has been proposed. Despite tissue heterogeneity in the SOS's output (vasomotion versus neurosecretion), O2-sensitive K+ channels constitute a conserved effector mechanism. Disorders of the O2-sensing may contribute to diseases, such as pulmonary hypertension.

Original languageEnglish (US)
Title of host publicationSignalling Pathways in Acute Oxygen Sensing
Pages157-171
Number of pages15
Volume272
StatePublished - 2006

Publication series

NameNovartis Foundation Symposium
Volume272
ISSN (Print)15282511

Keywords

  • HPV role in health and disease
  • Hypoxic pulmonary vasoconstriction (HPV)
  • Oxygen-sensing K channels
  • REDOX model and HPV
  • Specialized O2-sensing system (SOS)

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