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Molecular Identification of O2 Sensors and O2-Sensitive Potassium Channels in the Pulmonary Circulation

  • Chapter
Oxygen Sensing

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 475))

Abstract

Small, muscular pulmonary arteries (PAs) constrict within seconds of the onset of alveolar hypoxia, diverting blood flow to better-ventilated lobes, thereby matching ventilation to perfusion and optimizing systemic PO2. This hypoxic pulmonary vasoconstriction (HPV) is enhanced by endothelial derived vasoconstrictors, such as endothelin, and inhibited by endothelial derived nitric oxide. However, the essence of the response is intrinsic to PA smooth muscle cells in resistance arteries (PASMCs). HPV is initiated by inhibition of the Kv channels in PASMCs which set the membrane potential (BM). It is currently uncertain whether this reflects an initial inhibitory effect of hypoxia on the K+ channels or an initial release of intracellular Ca2+, which then inhibits K+ channels. In cither scenario, the resulting depolarization activates L-type, voltage gated Ca2+ channels, which raises cytosolic calcium levels [Ca+], and causes vasoconstriction. Nine families of Kv channels are recognized from cloning studies (Kv1–Kv9), each with subtypes (i.e. Kv1.1–1.6). The contribution of an individual Kv channel to the whole-cell current (IK) is difficult to determine pharmacologically because Kv channel inhibitors arc nonspecific. Furthermore, the PASMC’s IK, is an ensemble, reflecting activity of several channels. The K+ channels which set BM, and inhibition of which initiates HPV, conduct an outward current which is slowly inactivating, and which is blocked by the Kv inhibitor 4-aminopyridine (4-AP) but not by inhibitors of Ca+-or ATP-sensitive K+ channels. Using anti-Kv antibodies to immunolocalize and inhibit Kv channels, we showed that the PASMC contains numerous types of Kv channels from the Kv1and Kv2 families., Furthermore Kv1.5 and Kv2.1 may be important in determining the BM and play a role as effectors of HPV in PASMCs. While the Kv channels in PASMCs are the “effectors” of HPV, it is uncertain whether they are intrinsically O2-sensitive or arc under the control of an “O2 sensor”. Certain Kv channels are rich in cysteine, and respond to the local redox environment, tending to open when oxidized and close when reduced. Candidate sensors vary the PASMC redox potential in proportion to O2. These include Nicotinamide Adenine Dinucleotide Phosphate Oxidase, (NADPH oxidase) and the cytosolic ratio of reduced/oxidized redox couples (i.e. glutathione GSH/GSSG), as controlled by electron flux in the mitochondrial electron transport chain (ETC). Using a mouse that lacks the gp91phox component of NADPH oxidase, we have recently shown that loss of the gp91phox-containing NADPH oxidase as a source of activated oxygen species does not impair HPV. However, inhibition of complex 1 of the mitochondrial electron transport chain mimics hypoxia in that it inhibits IK, reduces the production of activated O2 species and causes vasoconstriction. We hypothesize that a redox O2 sensor, perhaps in the mitochondrion, senses O2 through changes in the accumulation of freely diffusible electron donors. Changes in the ratio of reduced/oxidized redox couples, such as NADH/NAD+ and glutathione (GSH/GSSG) can reduce or oxidize the K+ channels, resulting in alterations of PA tone.

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Authors and Affiliations

  1. Department of Medicine and Physiology, University of Alberta, Canada

    S L. A & E M

  2. Department of Cardiology, University of Minnesota, Minnesota, USA

    E. K W

  3. Department of Physiology and Medicine, University of Minnesota, Minnesota, USA

    H L. R

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Editors and Affiliations

  1. University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

    Sukhamay Lahiri  & Robert E. Forster II  & 

  2. Case Western Reserve University, Cleveland, Ohio

    Naduri R. Prabhakar

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A, S.L., W, E.K., R, H.L., M, E. (2002). Molecular Identification of O2 Sensors and O2-Sensitive Potassium Channels in the Pulmonary Circulation. In: Lahiri, S., Prabhakar, N.R., Forster, R.E. (eds) Oxygen Sensing. Advances in Experimental Medicine and Biology, vol 475. Springer, Boston, MA. https://doi.org/10.1007/0-306-46825-5_21

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  • DOI: https://doi.org/10.1007/0-306-46825-5_21

  • Publisher Name: Springer, Boston, MA

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