Adenosine Modulates ERK1/2, PI3K/Akt, and p38MAPK Activation in the Brain of the Anoxia-Tolerant Turtle <i>Trachemys Scripta</i>

Milton, Sarah L.; Dirk, Lynda J; Kara, Laurie; Prentice, Howard

doi:10.1038/jcbfm.2008.45

Cited by 21 publications

(46 citation statements)

References 43 publications

(68 reference statements)

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“…AKT is also activated after ischemia-reperfusion injury in the heart (18) and brain (38), and blocking AKT abolishes the protective effect of ischemic preconditioning in the heart (17). Moreover, AKT seems to be transiently phosphorylated in the initial phase of anoxia in warm-acclimated turtles (37). The observed reduction in AKT phosphorylation during long-term anoxia in the crucian carp may seem counterintuitive given its role as an important survival kinase in ischemic mammalian systems.…”

Section: Discussionmentioning

confidence: 96%

“…AKT is known to be activated after retinal injury in goldfish (29) and is phosphorylated in the frog (Rana perezi) liver during hypoxia (3). Interestingly, it was recently shown that the total level of AKT was increased in anoxic turtle (Trachemys scripta) brain, and the phosphorylation was higher and lower compared with normoxic control at 1 and 4 h of anoxia, respectively (37). AMPK has been shown to be phosphorylated in the liver of hypoxic frogs (Rana perezi), but not in the liver or skeletal muscle of anoxic wood frogs (Rana sylvatica) (51).…”

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confidence: 99%

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Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius)

Stensløkken

Ellefsen²,

Stecyk³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Stensløkken KO, Ellefsen S, Stecyk JAW, Dahl MB, Nilsson GE, Vaage J. Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius). Am J Physiol Regul Integr Comp Physiol 295: R1803-R1814, 2008. First published October 15, 2008 doi:10.1152/ajpregu.90590.2008.-We investigated whether two kinases critical for survival during periods of energy deficiency in anoxia-intolerant mammalian species, AMP-activated kinase (AMPK), and protein kinase B (AKT), are equally important for hypoxic/anoxic survival in the extremely anoxia-tolerant crucian carp (Carassius carassius). We report that phosphorylation of AMPK and AKT in heart and brain showed small changes after 10 days of severe hypoxia (0.3 mg O 2/l at 9°C). In contrast, anoxia exposure (0.01 mg O2/l at 8°C) substantially increased AMPK phosphorylation but decreased AKT phosphorylation in carp heart and brain, indicating activation of AMPK and deactivation of AKT. In agreement, blocking the activity of AMPK in anoxic fish in vivo with 20 mg/kg Compound C resulted in an elevated metabolic rate (as indicated by increased ethanol production) and tended to reduce energy charge. This is the first in vivo experiment with Compound C in a nonmammalian vertebrate, and it appears that AMPK plays a role in mediating anoxic metabolic depression in crucian carp. Real-time RT-PCR analysis of the investigated AMPK subunit revealed that the most likely composition of subunits in the carp heart is ␣ 2, ␤1B, ␥2a, whereas a more even expression of subunits was found in the brain. In the heart, expression of the regulatory ␥ 2-subunit increased in the heart during anoxia. In the brain, expression of the ␣ 1-, ␣2-, and ␥1-subunits decreased with anoxia exposure, but expression of the ␥ 2-subunit remained constant. Combined, our findings suggest that AMPK and AKT may play important, but opposing roles for hypoxic/anoxic survival in the anoxia-tolerant crucian carp. metabolism; hypoxia; ATP; ADP; ethanol ANOXIA TOLERANCE IN VERTEBRATES is limited to a few species, the most extreme being the crucian carp (Carassius carassius) and the freshwater turtles (genera Trachemys, Chrysemys, and Chelydra). These ectothermic animals can survive for months without oxygen at temperatures near 0°C (43,50). A key to survival in prolonged anoxia is the successful matching of ATP demand to the limited ATP production from anaerobic glycolysis. The anoxia-tolerant species appear to have evolved different strategies to meet this challenge (32). The turtle is strongly metabolically depressed during anoxia, with a drastically suppressed rate of ATP-turnover. Anoxic Carassius also decreases metabolic rate, but to a more moderate extent (62).The anoxic carp also upregulates glycolysis to match ATP supply and demand (33), but has evolved a unique strategy of producing ethanol as the major end product of anaerobic glycolysis (56). Ethanol is released to the surrounding water to avoid severe acidosis (42), and liver glycogen content is likely...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius)

Stensløkken

Ellefsen²,

Stecyk³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Because the downregulation of energy pathways and protection against cell death and oxidative stress are hallmarks of anoxia tolerance, it is not surprising to find evidence of p53 activation in the turtle (Zhang et al, 2013). Interestingly, there is also cross-talk between p53 and the phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) pathway (Ladelfa et al, 2011), which is upregulated in the anoxic turtle brain (Milton et al, 2008;Nayak et al, 2011).…”

Section: Neuroprotection At the Molecular Levelmentioning

confidence: 99%

“…Activated PI3K/AKT and extracellular regulated kinase (ERK1/2), generally considered to be cytoprotective, increase in turtle neurons in vivo (Milton et al, 2008) and in vitro (Nayak et al, 2011), as does Bcl-2. AKT is thought to work in part through interactions with the Bcl-2 family of proteins (Wang et al, 2007), and as with other components of anoxic survival, these pathways are linked to increases in adenosine.…”

Section: Neuroprotection At the Molecular Levelmentioning

confidence: 99%

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

Larson

Drew

Folkow

et al. 2014

Journal of Experimental Biology

129

102

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Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxiatolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy.KEY WORDS: Arctic ground squirrel, Cetacean, Hypoxia, Naked mole-rat, Seal, Turtle IntroductionEnvironmental conditions vary enormously for vertebrates, both with respect to the extreme conditions tolerated by a given species at different times and with respect to average living conditions tolerated by different species. Temperature is perhaps the most obvious example: from the poles to the equator, average ambient temperatures vary widely and have been accompanied by physiological adaptations appropriate to resident species; seasonal variations in temperature and resource variability can induce dramatic changes in physiological and/or behavioral patterns including migration and hibernation. Oxygen levels also vary widely, with animals adapted to sea level, high-altitude, underground and aquatic habitats. Oxygen levels can also change dramatically on a shorter-term basis, as can occur in tidal pools or in breath-hold divers. Approximately 20% of the oxygen consumed by the human body is used by the brain. The greater part of this oxygen is used to produce the ATP required to maintain the membrane potentials necessary for electrical signaling with synaptic and action potentials (Harris et al., 2012). In many vertebrates, including adult humans, interruption of the oxygen supply to the brain for more than a few minutes leads to irreversible neurological damage, including neuronal death. Without oxidative phosphorylation, ATP-dependent neuronal processes including ion transport and neurotransmitter reuptake decline sharply. Without pumping, ion gradients fail and neurons depolarize, releasing excessive levels...

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“…Both proapoptotic pathways (JNK and p38MAPK) and ostensible survival pathways (ERK and AKT) are activated simultaneously in response to cellular stress in mammalian cells [32]. The turtle brain, however, again shows a robust protective response; ERK and AKT are strongly upregulated in the anoxic brain, but with a marked suppression of p38MAPK [64]. In mammalian models, DOR-mediated HPC protection has also been related to increases in ERK and Bcl-2 activity, thus counteracting detrimental hypoxic increases in p38MAPK activity and cytochrome C release [65,66].…”

Section: Anoxia Tolerance and Ischemic Pc Share Common Mechanismsmentioning

confidence: 99%

Alleviating Brain Stress: What Alternative Animal Models Have Revealed About Therapeutic Targets For Hypoxia and Anoxia

Milton

2013

Future Neurol.

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While the mammalian brain is highly dependent on oxygen, and can withstand only a few minutes without air, there are both vertebrate and invertebrate examples of anoxia tolerance. One example is the freshwater turtle, which can withstand days without oxygen, thus providing a vertebrate model with which to examine the physiology of anoxia tolerance without the pathology seen in mammalian ischemia/reperfusion studies. Insect models such as Drosophila melanogaster have additional advantages, such as short lifespans, low cost and well-described genetics. These models of anoxia tolerance share two common themes that enable survival without oxygen: entrance into a state of deep hypometabolism, and the suppression of cellular injury during anoxia and upon restoration of oxygen. The study of such models of anoxia tolerance, adapted through millions of years of evolution, may thus suggest protective pathways that could serve as therapeutic targets for diseases characterized by oxygen deprivation and ischemic/reperfusion injuries.

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Adenosine Modulates ERK1/2, PI3K/Akt, and p38MAPK Activation in the Brain of the Anoxia-Tolerant Turtle Trachemys Scripta

Cited by 21 publications

References 43 publications

Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius)

Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius)

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

Alleviating Brain Stress: What Alternative Animal Models Have Revealed About Therapeutic Targets For Hypoxia and Anoxia

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