Adaptive responses of vertebrate neurons to hypoxia
1 Department of Anesthesia and Perioperative Care, University of California,
San Francisco, CA 94143-0542 USA
2 Department of Physiology, University of Otago, Dunedin, New
Zealand
* Author for correspondence (e-mail: BicklerP{at}anesthesia.ucsf.edu)
Accepted 23 August 2002
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Summary |
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Key words: neuron, hypoxia, oxygen sensor, intracellular calcium, vertebrate
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Introduction |
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Neurons vary widely in their capacity to adapt to a limited oxygen supply to the brain, reflecting the diversity of neuronal functions and the degree of hypoxia normally experienced. This review will define some of the major gaps in our understanding of this adaptive ability in vertebrate neurons. We will specifically review evidence for cellular oxygen sensors, ion channel arrest and metabolic suppression, and oxygen-sensitive signal transduction processes that modulate survival. As will be apparent, huge gaps remain in our knowledge of these adaptations and abundant opportunities exist to ameliorate this knowledge deficit.
Examining the responses of hypoxia-tolerant neurons to decreased oxygen availability is of interest for several reasons. First, oxygen signaling is well developed in hypoxia-tolerant neurons, making them ideal models for studying signal transduction processes during adaptations to hypoxia. Second, hypoxia-tolerant neurons are useful models for distinguishing between injury and adaptation induced by hypoxia. This is of obvious interest in determining the relevance of proposed therapeutic interventions for patients with hypoxic or ischemic diseases. Third, these neurons may help in the identification of entirely new targets for treating diseases that involve hypoxia.
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Where are hypoxia-tolerant neurons found? |
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Hypoxia-tolerant fishes such as carp contrast with turtles in that their
neurons apparently maintain a higher state of vigilance during anoxia, i.e.
the brain remains active (Nilsson,
2001). Other fishes, such as estivating African lungfish, enter
dormant, suspended animation states during dry periods, which are possibly
associated with at least some degree of hypoxia. Numerous fish species reside
in the oxygen-depleted waters of the Amazon basin and these species offer
exciting opportunities for exploration...
Adult amphibians may experience low ambient oxygen during retreats to
burrows, cocoons or other refugia during dry seasons (e.g. the Australian frog
Cyclorana platycephala or the American spadefoot toad Scaphiopus
couchii), although the degree of hypoxia they encounter is probably not
extreme. Spadefoot toads decrease metabolism substantially during dormancy and
some information is available on the regulation of their hypometabolic
condition (Storey, 2002).
Species that spend the winter dormant in hypoxic water have also been of
interest. The protective effect of metabolic rate depression during cold
hypoxic submergence has been demonstrated in adult hibernating Rana
temporaria (Donohoe et al.,
2000
). Rana brain maintains ATP levels for 2 days at
3°C in anoxia before declining (P. H. Donohoe and R. G. Boutilier,
unpublished data). Throughout all stages of prolonged hypoxia (water
PO2 30-60 mmHg), for up to 16 weeks at 3°C,
frog brain ATP levels were maintained, although briefer anoxia at 25°C is
associated with ATP loss (Knickerbocker
and Lutz, 2001
). The ability to depress metabolic rate such that
ATP demands can be met by oxidative phosphorylation in an oxygen-limited
environment is probably the key to the frogs' overwintering survival. Tadpoles
may be good models for studies on the effects of hypoxia on the brain because
some species are hypoxia tolerant (West
and Burggren, 1982
) and the cells of the central nervous system
are relatively accessible for study.
Numerous mammals are hypoxia tolerant. The naked Kenyan mole rat
Hetercephalus glaber, which lives in a burrow environment of approx.
8% oxygen, is a noteworthy example. Synaptic transmission in the mole rat
hippocampus is very tolerant of low oxygen and recovers quickly from anoxia
(J. Larsen and T. Park, unpublished data). Cortical and hippocampal neurons
from oxygen-sensitive species such as Rattus norvegicus are
hypoxia-tolerant during the embryonic and neonatal periods
(Adolph, 1948;
Bickler and Hansen, 1998
;
Haddad and Donnelley, 1990
;
Haddad and Jiang, 1993
). This
is not surprising because oxygen tension in fetal brain is less than half the
normal value for adults (Parer,
1993
). In some species the birth process or the nesting
environment may be associated with hypoxia. Mammalian hibernation is
associated with tolerance of hypoxia or ischemia, although hibernation is
neither ischemic or hypoxic, since blood flow and metabolism are decreased in
parallel and lactic acid does not accumulate
(Hochachka and Guppy, 1987
).
Neurons from hibernating ground squirrels tolerate hypoxia-glucose deprivation
even when studied at 37°C, suggesting that hypothermia is but one factor
in the tolerance of this tissue (Frerichs,
1999
).
Little is known mechanistically concerning the adaptation of marine mammals
to the brain hypoxia that accompanies deeper, long-duration dives, even though
their tolerance is well defined (Elsner et
al., 1972; Lutz and Nilsson,
1997b
). Hypometabolism occurs during diving in seals
(Hurley and Costa, 2001
) and
it would be fascinating to determine if portions of the brain participate in
energy savings by undergoing a reduction in activity during long dives.
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Why does the lack of O2 kill typical neurons rapidly? |
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When oxygen or blood flow to the mammalian brain decreases to critical
levels, energy failure occurs, with a decline in ATP by as much as 90% in as
little as 5 min (Erecinska and Silver,
2001). When 50-65% of the ATP is lost, depolarization of the
membrane and subsequent uptake of sodium and water occurs
(Hansen, 1985
;
Knickerbocker and Lutz, 2001
).
Depolarization causes Ca2+ influx through voltage-gated
Ca2+ channels. The Na+ gradient collapse causes the
sodium-glutamate cotransporters to eject glutamate into the extracellular
space (Rossi et al., 2000
).
Glutamate triggers vigorous activation of glutamate receptors, initiating a
process of calcium influx and excitatory injury called the glutamate cascade.
N-methyl-D-aspartate glutamate receptors are responsible for a
significant part of the Ca2+ influx and the
Ca2+-dependent cell injury that ensue
(Lee et al., 1999
). Glutamate
receptors have been primary targets for experimental treatment of ischemic
brain injury (Choi, 1995
;
Lee et al., 1999
). The death
of neurons from these insults can follow quickly from swelling and lysis
(necrosis) or evolve over many days. This slower cell death is complex and in
some respects resembles programmed cell death or apoptosis. An excellent
review of the role of programmed cell death in brain ischemia was recently
published (Lipton, 1999
).
A most fundamental adaptive response of hypoxia-tolerant cells to oxygen
lack is the capacity to avoid a drastic decline in ATP levels at a time of
absent aerobic ATP production. It is likely that similar responses to
energetic stress are found in cells during hibernation and estivation,
although hypoxia does not characterize these states. A drastic, balanced,
suppression of ATP demand and supply pathways must occur in all these
conditions; this regulation allows ATP levels to remain relatively constant,
even while ATP turnover rates greatly decline. In neurons, the ATP
requirements of ion pumping (mainly Na+;
Rolfe and Brown, 1997) are
downregulated by `channel' arrest (Bickler
et al., 2002
). The ATP demands of protein synthesis also must be
downregulated, and although rapid and global suppression of protein synthesis
occurs in anoxia-adapted hepatocytes
(Hochachka et al., 1996
), we
think it likely that selective rather than global suppression of gene
expression and protein synthesis occurs in neurons. This necessitates that a
significant percentage of the neurons in the brain are functionally
inactivated during anoxia, therefore cannot participate in vigilance or
regulation activities. Accordingly, `metabolic arrest' cannot be the only
cellular response for vertebrate neurons some neuron groups must
remain `vigilant' and participate in regulation and eventual arousal from
dormancy/inactivity. Indeed, a report by Fernandes et al.
(1997
) shows that
electroencephalograph activity in anoxic turtles waxes and wanes over periods
of many hours.
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Sensing the lack of oxygen |
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|
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Some of the effects of O2 on ion channels may be mediated by
membrane proteins containing heme groups or redox-sensitive sites such as
NADPH oxidase (Prabhakar and Overholt,
2000), where the redox state of the oxidase controls ion flux or
other effects (Fig. 1).
Perhaps the best-described O2-sensing pathway is the
oxygen-sensitive transcription factor HIF, which is regulated by a series of
at least two oxygen-sensitive hydroxylases
(Lando et al., 2002). HIF has
been reviewed recently (Semenza,
1999
) and will not be extensively discussed here.
A less studied hypoxia-modulated transcription factor is NFkB, which may be
activated both by extracellular signals such as cytokines and intracellular
signals such as reactive oxygen (ROS)
(Haddad and Land, 2000).
Oxygen sensors associated with heme proteins such as cytochrome c in
the mitochondria may respond to hypoxia by altering the rate of release of
reactive oxygen species that activate transcription factors
(Bunn and Poyton, 1996
;
Vanden Hoek et al., 1998
).
A convergent pathway for the regulation of multiple modalities involved in
O2 sensing is the mitogen-activated protein kinase system (MAPK),
which is composed of different cassettes terminating in a variety of
transcription factors. Interestingly, the MAPK ERK1/2 modulates HIF-1a by
posphorylation control (Minet et al.,
2000). Extracellular growth factor signals strongly influence the
activity of HIF, probably through the MAPK system
(Semenza, 1999
).
Recent evidence suggests that membrane-bound phospholipase C may play a
role in transducing the signal of hypoxia into alterations in the
phosphorylation state of MAP kinase. In our laboratory, we found that
phosphorylation of the MAPK kinase p42/42 (associated with neuroprotective
gene expression induced by agents such as growth factors) occurs during
hypoxia and that it depends on phospholipase C and intracellular calcium
(Donohoe et al., 2001).
In summary, oxygen sensing is achieved by a variety of molecules whose effects are complexly intertwined. Evidence exists for rapid and longer-term effects of such signaling, as described below.
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Putting the signal for lack of oxygen to work |
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Acute responses to hypoxia |
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An important feature of these controls is that they operate over a wide range of time scales and are thus suited to variations in the duration of hypoxia.
Some oxygen-sensitive ion channels may have oxygen sensors directly
associated with the channel. In the rat kVß2 channel the ß subunit
is an oxidoreductase that includes a nicotinamide cofactor
(Bahring et al., 2001). The
oxidoreductase apparently s directly with the voltage sensing portion of the
channel, influencing its activity depending on oxygen tension.
Table 1 lists some known
effects of oxygen on ion channel regulation.
Acute responses: Interaction of bioenergetics and
[Ca2+]i
Intracellular calcium plays a major role in controlling many cellular
processes (e.g. synaptic plasticity, neurotransmitter release, cell
proliferation and cell survival; for review, see
Berridge et al., 2000). At the
subcellular level, calcium acts as a second messenger, which modulates
processes such as the release of intracellular calcium stores, gene
transcription and function of protein kinases and phosphatases. Transient
increases in [Ca2+]i are required for normal cell
functioning, but sustained increases in [Ca2+]i above
200 nmol l-1 are usually considered pathological in neurons
(Lee et al., 1999
).
Mitochondria contribute to [Ca2+]i homeostasis by acting as a calcium source or `sink' when cytosolic calcium reaches inadequate or excessive levels. Mitochondrial Ca2+ homeostasis is tightly coupled to ATP production during hypoxia because Ca2+ accumulates in the matrix when electron transport is uncoupled from oxidative phosphorylation. Calcium accumulation contributes to the depolarization of the mitochondrial membrane potential.
Depolarisation-transcriptional coupling
Ca2+ is also an important regulator of gene expression. Global
elevations of [Ca2+]i, acting via calmodulin,
control the rapid gene expression triggered by neuronal depolarisation
(Millhorn et al., 2000).
Hardingham et al. (2001
)
suggest that a second, rapidly responding, excitationtranscription
transduction pathway exists in neurons, whereby [Ca2+]
microdomains, located proximal to NMDA receptors, remotely affect nuclear
[Ca2+], which is the central regulator of transcription. They
demonstrate that the discrete elevation in [Ca2+], restricted to
the site of entry in the synapse, is propagated independently of a global
elevation in [Ca2+] to the nucleus by an extracellular
signal-regulated kinase (ERK1/2).
Acute suppression of metabolism
Survival of long-term anoxia requires that neurons decrease their substrate
utilization so as to avoid energy depletion. In neurons, little is known about
how this is done. Much more is known about regulation of substrate utilization
in dormant, aerobic states such as estivation in land snails or in
hibernators. Studies in these non-hypoxic but metabolically quiescent animals
have clearly shown that hypometabolism is associated with phosphorylation
control of glycolytic enzymes (Storey,
2002). Whether this principle applies during hypoxic dormancy has
not been determined, but it seems reasonable that it does. The signals that
initiate the activation of protein kinases or phosphatases have not been
identified. Phosphorylation controls are probably but one aspect of a
hypometabolic state in dormant animals.
Bishop et al. (2001) have
examined how dormancy influences mitochondrial function in land snail
hepatopancreas cells. They observed that 75% of the decline in oxidative
respiration observed during aestivation is due to a drop in oxidative
respiratory enzyme kinetics, i.e. a fall in activity of the proteins that
produce the mitochondrial membrane potential (
m). The
lowered
m results in a subordinate decline in the
oxidative respiration driving ATP production.
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Long-term responses: transcriptional regulation |
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Are responses to hypoxia adaptive or injurious? |
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Hypoxia-tolerant neurons have much to teach about the tolerable limits of
alterations in energy state and cellular homeostasis simple because
deleterious changes develop slowly and are thus easier to observe. For
example, ATP loss from anoxic frog brain evolves over hours to days, not
minutes, making events associated with it easy to chronicle
(Knickerbocker and Lutz,
2001). New insights can also be obtained about events that may be
part of an injury process or part of survival. A good example is the complex
process of apoptosis. In recent studies in our laboratory, we found that
pro-apoptotic proteins such as Bax are expressed in the turtle brain during
prolonged, but survivable, hypoxia. This raises the possibility that either
proteins such as Bax actually have a protective side to them or that certain
neurons are deciduous they may die during anoxic dormancy and
regenerate in the spring with resumption of aerial respiration. Death of cells
almost certainly occurs in many tissues of the body because the mortality from
months of hypoxia is large perhaps up to 30% of turtles die each year
during dormancy. At the same time, inhibition of apoptosis may be important to
other neurons during dormancy, despite conditions that might otherwise be
associated with the triggering of cell death processes. The status of
regeneration in the turtle brain following prolonged dormancy will be
fascinating to study.
The role of the MAPK signaling system in the regulation of apoptosis is
also fertile ground for study. MAPKs regulate the balance between cell
survival/differentiation and cell death/apoptosis. The p42/p44 MAPKs (involved
in the ERK pathway) is activated by processes that promote neuron survival
(e.g. by neuroprotective growth factors such as BDNF;
Nicole et al., 2001). In
contrast, the p38 pathway is associated with neuron death. Notably, the
p42/p44 (also termed ERK) pathway is activated by small increases in
[Ca2+]i during survivable degrees of hypoxia
(Minet et al., 2000
).
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The importance of recovering well from lack of oxygen |
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Little is known concerning the issue of how cells in a profound state of dormancy can resume normal activities when favorable environmental conditions return. One hypothesis is that some groups of neurons remain in a vigilant state and are capable of arousing others when appropriate. The signaling events which orchestrate these processes are largely unstudied.
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Major unanswered questions |
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References |
---|
Adolph, E. (1948). Tolerance to cold and anoxia
in infant rats. Am. J. Physiol.
155,366
-377.
Bahring, R., Milligan, C., Vardanyan, V., Engeland, B., Young,
B., Dannenberg, J., Waldschutz, R., Edwards, J., Wray, D. and Pongs, O.
(2001). Coupling of voltage-dependent potassium channel
inactivation and oxidoreductase active site of Kvbeta subunits. J.
Biol. Chem. 276,22923
-22929.
Bergeron, M., Yu, A. Y., Solway, K. E., Semenza, G. L. and Sharp, F. R. (1999). Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur. J. Neurosci. 11,4159 -4170.[Medline]
Berridge, M., Lipp, P. and Bootman, M. (2000). The versatility and universality of calcium signaling. Nat. Rev. Mol. Cell Biol. 1,11 -21.[Medline]
Bickler, P. E., Donohoe, P. H. and Buck, L. T.
(2000). Hypoxia-induced silencing of NMDA receptors in turtle
neurons. J. Neurosci.
20,3522
-3528.
Bickler, P. E., Donohoe, P. H. and Buck, L. T. (2002). Molecular adaptations for survival during anoxia: lessons from lower vertebrates. Neurosci. 8, 234-242.
Bickler, P. E. and Hansen, B. M. (1998). Hypoxia-tolerant neonatal CA1 neurons: Relationship of survival to evoked glutamate release and glutamate receptor-mediated calcium changes in hippocampal slices. Dev. Brain Res. 106, 57-69.[Medline]
Bishop, T., St.-Pierre, J. and Brand, M.
(2001). Primary causes of decreased mitochondrial oxygen
consumption during metabolic suppression in snail cells. Am. J.
Physiol. Regul. Integr. Comp. Physiol.
282,R372
-R382.
Buck, L. T. and Bickler, P. E. (1998). Adenosine and anoxia reduce N- methyl-D-aspartate receptor open probability in turtle cerebrocortex. J. Exp. Biol. 210,289 -297.
Bunn, H. and Poyton, R. (1996). Oxygen sensing
and molecular adaptation to hypoxia. Physiol. Rev.
76,839
-885.
Choi, D. W. (1995). Calcium: still center stage in hypoxic-ischemic neuronal death. Trends Neurosci. 18, 58-60.[Medline]
Crocker, C., Ultsch, G. and Jackson, D. C. (1999). The physiology of diving in a north-temperate and three tropical turtle species. J. Comp. Physiol. B 169,249 -255.[Medline]
Donohoe, P. H., Fahlman, C. S., Bickler, P. E., Vexler, Z. S. and Gregory, G. A. (2001). Neuroprotection and intracellular Ca2+ modulation with fructose- 1,6-bisphosphate during in vitro hypoxia-ischemia involves phospholipase C-dependent signaling. Brain Res. 917,158 -166.[Medline]
Donohoe, P. H., West, T. G. and Boutilier, R. G.
(2000). Factors affecting membrane permeability and ionic
homeostasis in the cold-submerged frog. J. Exp. Biol.
203,405
-414.
Elsner, R., Shurley, J. T., Hammond, D. D. and Brooks, R. E. (1972). Cerebral tolerance to hypoxemia in asphyxiated Weddell seals. Resp. Physiol. 9,287 -297.
Erecinska, M. and Silver, I. A. (2001). Tissue oxygenation and brain sensitivity to hypoxia. Resp. Physiol. 128,263 -276.[Medline]
Fearon, I. M., Palmer, A. C., Balmforth, A. J., Ball, S. G.,
Varadi, G. and Peers, C. (1999). Modulation of recombinant
human cardiac L-type Ca2+ channel alpha 1C subunits by redox agents
and hypoxia. J. Physiol.
514,629
-637.
Fearon, I. M., Randall, A. D., Perez-Reyes, E. and Peers, C. (2000). Modulation of recombinant T-type Ca2+ channels by hypoxia and glutathione. Pflugers Arch - Eur. J. Physiol. 441,181 -188.
Fernandes, J. A., Lutz, P. L., Tennenbaum, A., Todorov, A. T.,
Liebovitch, L. and Vertes, R. (1997). Electroencephalogram
activity in the anoxic turtle brain. Am. J. Physiol.
273,R911
-R919.
Frerichs, K. U. (1999). Neuroprotective strategies in nature novel clues for the treatment of stroke and trauma. Acta Neurochirugica Suppl. 73, 57-61.
Ghai, H. S. and Buck, L. T. (1999). Acute
reduction in whole cell conductance in anoxic turtle brain. Am. J.
Physiol. 277,R887
-R893.
Haddad, G. and Donnelley, D. (1990). O2 deprivation induces a major depolarization in brain stem neurons in adult but not in the neonatal rat. J. Physiol. 429,411 -428.[Abstract]
Haddad, G. and Jiang, C. (1993). O2 deprivation in the central nervous system: On mechanisms of neuronal response, sensitivity, and injury. Progr. Neurobiol. 40,277 -318.[Medline]
Haddad, J. J. and Land, S. C. (2000).
O2-evoked regulation of HIF-1 and NF-
B in perinatal
lung epithelium requires glutathione biosynthesis. Am. J. Physiol.
Lung Cell. Mol. Physiol. 278,L492
-L503.
Hammarstrom, A. K. M. and Gage, P. W. (2000). An oxygen-sensing sodium channel in rat hippocampal neurons. Biophys. J. 78,88A .
Hansen, A. (1985). Extracellular potassium concentration in juvenile and adult brain cortex during anoxia. Acta Physiol. Scand. 99,412 -428.
Hardingham, G. E., Arnold, F. J. L. and Bading, H. (2001). A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication. Nature Neurosci. 4,565 -566.[Medline]
Hermes-Lima, M. and Storey, K. B. (1996). Antioxidant defences in the tolerance of freezing and anoxia by garter snakes. Am. J. Physiol. 265,R646 -R652.
Hochachka, P. (1986). Defense strategies against hypoxia and hypothermia. Science 231,234 -241.[Medline]
Hochachka, P., Buck, L., Doll, C. and Land, S.
(1996). Unifying theory of hypoxia tolerance: Molecular/metabolic
defense and rescue mechanisms for surviving oxygen lack. Proc.
Natl. Acad. Sci. USA 93,9493
-9498.
Hochachka, P. W. and Guppy, M. (1987). Metabolic Arrest and The Control of Biological Time. Cambridge, MA: Harvard University Press.227 pp.
Hochachka, P. W. and Lutz, P. (2001). Mechanism, origin, and evolution of anoxia tolerance in animals. Comp. Biochem. Physiol. B. 130,435 -459.[Medline]
Hurley, J. and Costa, D. (2001). Standard
metabolic rate at the surface and during trained submersions in adult
California sea lions (Zalophus californianus). J. Exp.
Biol. 204,3273
-3281.
Knickerbocker, D. L. and Lutz, P. L. (2001).
Slow ATP loss and the defense of ion homeostasis in the anoxic frog brain.
J. Exp. Biol. 204,3547
-3551.
Lando, D., Peet, D., Whelan, D., Gorman, J. and Whitelaw, M.
(2002). Asparagine hydroxylation of the HIF transactivation
domain: a hypoxic switch. Science
295,858
-861.
Lee, J.-M., Zipfel, G. J. and Choi, D. W. (1999). The changing landscape of ischaemic brain injury mechanisms. Nature 399(suppl.), A7-A14.[Medline]
Lewis, A., Hartness, M. E., Chapman, C. G., Fearon, I. M., Meadows, H. J., Peers, C. and Kemp, P. J. (2001). Recombinant hTASK1 is an O2-sensitive K+ channel. Biochem. Biophys. Res. Comm. 285,1290 -1294.[Medline]
Lipton, P. (1999). Ischemic cell death in brain
neurons. Physiol. Rev.
79,1431
-1567.
Lutz, P. (1992). Mechanisms for anoxic survival in the vertebrate brain. Annu. Rev. Physiol 54,601 -618.[Medline]
Lutz, P. and Nilsson, G. (1997a). Contrasting
strategies for anoxic brain survivalglycolysis up or down.
J. Exp. Biol. 200,411
-419.
Lutz, P. L. and Nilsson, G. E. (1997b). The Brain Without Oxygen: Causes of Failure and Mechanisms for Survival. Austin: R. G. Landis.227 pp.
Mattson, M. P. (1997). Neuroprotective signal transducition: Relevance to stroke. Neurosci. Biobehav. Rev. 21,193 -206.[Medline]
Millhorn, D., Beitner-Johnson, D., Conforti, L., Conrad, P., Kobayashi, S., Yuan, Y. and Rust, R. (2000). Gene regulation during hypoxia in excitable oxygen-sensing cells: depolarization-transcription coupling. Adv. Exp. Med. Biol. 475,131 -142.[Medline]
Minet, E., Arnould, T., Michel, G., Roland, I., Mottet, D., Raes, M., Remacle, J. and Michiels, C. (2000). ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett. 468,53 -58.[Medline]
Nicole, O., Ali, C., Docagne, F., Plawinski, L., MacKenzie, E.
T., Vivien, D. and Buisson, A. (2001). Neuroprotection
mediated by glial cell line-derived neurotrophic factor: involvement of a
reduction of NMDA-induced calcium influx by the mitogen-activated protein
kinase pathway. J. Neurosci.
21,3024
-3033.
Nilsson, G. E. (2001). Surviving anoxia with
the brain turned on. News Physiol. Sci.
16,217
-221.
Parer, J. T. (1993). Fetal uteroplacental circulation and respiratory gas exchange. In Anesthesia for Obstetrics (ed. S. M. Shnider and G. Levinson), pp.19 -28. New York: Williams and Wilkins.
Patel, A. J. and Honore, E. (2001). Molecular
physiology of oxygen-sensotive potassium channels. Eur. Resp.
J. 18,221
-227.
Perez-Pinzon, M., Rosenthal, M., Sick, T., Lutz, P., Pablo, J.
and Mash, D. (1992). Downregulation of sodium channels during
anoxia: a putative survival strategy of turtle brain. Am. J.
Physiol. 262,R712
-R715.
Porter, V. A., Rhodes, M. T., Reeve, H. L. and Cornfield, D.
N. (2001). Oxygen-induced fetal pulmonary vasodilation is
mediated by intracellular calcium activation of KCa channels.
Am. J. Physiol. Lung Cell. Mol. Physiol.
281,L1379
-L1385.
Prabhakar, N. R. and Overholt, J. L. (2000). Cellular mechanisms of oxygen sensing at the carotid body: heme proteins and ion channels. Resp. Physiol. 122,209 -221.[Medline]
Rice, M. E., Lee, E. J. and Choy, Y. (1995). High levels of ascorbic acid, not glutathione, in the CNS of anoxia-tolerant reptiles contrasted with levels in anoxia-intolerant species. J. Neurochem. 64,1790 -1799.[Medline]
Rolfe, D. F. S. and Brown, G. C. (1997).
Cellular energy utilization and molecular origin of standard metabolic rate in
mammals. Physiol. Rev.
77,731
-758.
Rossi, D. J., Oshima, T. and Attwell, D. (2000). Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403,316 -321.[Medline]
Semenza, G. L. (1999). Regulation of mammalian O2 homeostasis by hypoxia-inducible factor. 1. Annu. Rev. Cell Dev. Biol. 15,551 -578.[Medline]
Storey, K. B. (2002). Life in the slow lane: molecular mechanisms of estivation. Comp. Biochem. Physiol. (in press).
Ultsch, G. and Jackson, D. (1982). Long-term submergence at 3°C of the turtle Chrysemys picta belli, in normoxic and severely hypoxic water. I. Survival, gas exchange and acidbase status. J. Exp. Biol. 96, 11-28.
Vanden Hoek, T., Becker, L., Shao, Z., Li, C. and Schumacker,
P. (1998). Reactive oxygen species released from mitochondria
during brief hypoxia induce preconditioning in cardiomyocytes. J.
Biol. Chem. 273,18092
-18098.
West, N. and Burggren, W. (1982). Gill and lung ventilatory responses to steady-state aquatic hypoxia and hyperoxia in the bullfrog tadpole. Resp. Physiol. 47,165 -176.[Medline]