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ScienceWeek
CELL BIOLOGY: ON OXYGEN SENSORS
The following points are made by T. Hoshi and S. Lahiri (Science 2004 306:2050):
1) Animals require oxygen to survive, and have evolved different mechanisms to sense and respond to low oxygen tensions. When faced with low blood oxygen levels (hypoxia), humans and other mammals reflexively increase the lung ventilation rate to restore normal oxygen tensions to vital organs. This compensatory mechanism relies on oxygen-sensing glomus cells in the carotid body located in the carotid artery. Glomus cells sense hypoxia and respond by rapid membrane depolarization. This results in production of action potentials, influx of calcium ions (Ca2+) into the glomus cells through voltage-gated Ca2+ channels, and release of the neurotransmitter dopamine [1,2]. Dopamine then activates postsynaptic sensory neurons, and this afferent discharge initiates a variety of responses by the central nervous system that ensure appropriate oxygenation of different organs. But how does hypoxia induce the rapid depolarization of glomus cells? Williams et al [3] have answered three key questions that have kept investigators guessing: What is the oxygen sensor? What is the effector in glomus cells responsible for their depolarization? What is the messenger that couples the oxygen sensor to the effector?
2) Glomus cells are equipped with a full complement of ion channels, any of which could mediate rapid depolarization in response to hypoxia. Evidence suggests that many of these channels are regulated by hypoxia to different degrees, rendering a number of them potential oxygen-sensing effectors. Among them, however, is a large-conductance (Ca2+)- and voltage-gated potassium (BK) channel that may be particularly important. BK channels have extraordinarily large conductances, greater than 200 pS under some conditions. They are allosterically activated by intracellular Ca2+ ions and membrane depolarization. Under normal conditions, some BK channels are open and thus exert a negative influence on cell excitability by keeping the membrane in a hyperpolarized state [4]. Pharmacological blockers of BK channel activity induce depolarization similar to that observed with hypoxia [1,5].
3) Williams et al [3] performed electrophysiological experiments on native glomus cell BK channels as well as BK channels expressed in cultured mammalian cells (heterologous expression). They discovered that low oxygen tensions result in closure of the BK channels near the resting potential in excised patches of plasma membrane largely devoid of cytoplasmic components. This finding establishes BK channels as an important effector of the oxygen-sensing process in glomus cells.
4) What is the oxygen sensor in glomus cells and what couples the oxygen sensor to the BK channel effector? The observation that the inhibition of BK channels induced by hypoxia persists in excised membrane patches is crucial. This indicates that an intact cytoplasmic signaling cascade network is not essential, and that cellular constituents near the BK channel are sufficient for hypoxia-mediated inhibition of channel activity. Thus, the oxygen sensor that triggers BK channel inhibition must reside near the channel -- a signaling molecule could readily travel from the sensor to the channel. A recent study [3] showed that the BK channel's sensitivity to hypoxia may be mediated by another gas, carbon monoxide (CO), and that the underlying mechanism may involve an increasingly common principle in cellular signal transduction: a spatially tuned local signaling pathway mediated by a large protein complex.
References (abridged):
1. J. Lopez-Barneo et al., Annu. Rev. Physiol. 63, 259 (2001)
2. N. R. Prabhakar, J. Appl. Physiol. 88, 2287 (2000)
3. S. E. Williams et al., Science 306, 2093 (2004)
4. B. S. Rothberg, Sci. STKE 2004, pe16 (2004)
5. N. R. Prabhakar, J. L. Overholt, Respir. Physiol. 122, 209 (2000)
Science http://www.sciencemag.org
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MEDICAL BIOLOGY: OXYGEN AND NEOPLASMS
The following points are made by D.P. Bottaro and L.A. Liotta (Nature 2003 423:593):
1) When cells are starved of oxygen, they usually die. This is why numerous anti-cancer treatments aim to prevent the growth of blood vessels in tumors, thereby cutting off their oxygen supply. But in the latest addition to a long list of lessons we are learning about the insidious nature of cancer, it seems that tumors may in fact turn a lack of oxygen to their advantage: Pennacchietti et al (Cancer Cell 2003 3:347) have uncovered a molecular pathway that is switched on by low oxygen levels, and which could cause cancers to become more aggressive and invade surrounding tissues.
2) Normal tissues receive a constant supply of oxygen from oxygenated hemoglobin molecules, carried by a continuous flow of blood. When such tissues are subjected to oxygen starvation (hypoxia) -- because of a reduction either in blood flow or in the oxygen content of the blood -- the eventual result is cell death. Depending on their individual metabolic requirements, some tissues can survive a hypoxic state for longer than others; for example, brain tissue can survive if hypoxia is limited to only a few minutes. To ensure survival, tissues react in two ways: they switch into a protective mode by using a specific set of hypoxia-sensing proteins called "hypoxia-inducible factors", or HIFs; and they produce "angiogenesis" proteins that will attract new blood vessels as a way of restoring local blood flow.
3) Hypoxia has found a place on both sides of the war on cancer. On the one hand, the idea that depriving a primary tumour of essential nutrients and oxygen will stop its growth and spread has won wide appeal. When tumors reach a certain size they outgrow their blood supply, and various studies have linked the resulting hypoxia, via HIFs, to the production of vascular endothelial cell growth factor and consequent stimulation of blood-vessel growth. Following these findings, advocates of anti-angiogenesis strategies have looked for ways to block this molecular cascade by targeting the constituent signalling molecules or the responsive blood-vessel cells (endothelial cells). On the other hand, several clinical studies have shown that the presence of hypoxic regions within tumors correlates with poor prognosis and an increased risk of spread to other parts of the body (metastasis), irrespective of treatments used. These findings have cast a different light on tumour starvation as a therapeutic strategy.
Nature http://www.nature.com/nature
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VERTEBRATE SUSPENDED ANIMATION PRODUCED BY OXYGEN DEPRIVATION
The following points are made by P.A. Padilla and M.B. Roth (Proc. Nat. Acad. Sci. 2001 98:7331):
1) Most animals are very sensitive to reduced levels of oxygen. Known vertebrate responses to low oxygen concentration (hypoxia) include changes in carbohydrate metabolism, an increase in nitric oxide, and stimulation of red blood cell and hemoglobin production. Hypoxia can also induce the expression of a select set of genes, which include the genes for glycolytic enzymes, the glycoprotein hormone erythropoietin, and the inducible form of nitric oxide synthase. Extreme hypoxia is central to the pathology of several diseases involving cardiac and pulmonary dysfunction.
2) It has been demonstrated that some invertebrates (e.g., nematode worms, brine shrimp, fruit flies) have the ability to survive in the absence of molecular oxygen (anoxia). The brine shrimp A. franciscana has been shown to survive 4 years of continuous anoxia, exhibiting an arrest of development, a decrease in intracellular pH, a reduction in protein synthesis, and an accumulation of heat shock proteins. It has been demonstrated that both nematode worms (C. elegans) and fruit flies (D. melanogaster) can survive at least 1 day of anoxia exposure by arresting development until oxygen supply is reestablished.
3) The authors report that embryos of the zebrafish Danio rerio can survive for 24 hours in the absence of oxygen, and that the evidence indicates these embryos enter into a state of suspended animation where all microscopically observable movement ceases, including cell division, developmental progression, and motility. Animals that had developed a heartbeat before anoxic exposure showed no evidence of a heartbeat until return to terrestrial atmosphere.
Proc. Nat. Acad. Sci. http://www.pnas.org
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