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Am J Physiol Regul Integr Comp Physiol 285: R1317-R1321, 2003; doi:10.1152/ajpregu.00261.2003
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CARDIAC, RENAL, AND RESPIRATORY INTEGRATION

Gene transcription of brain voltage-gated potassium channels is reversibly regulated by oxygen supply

Howard M. Prentice,1 Sarah L. Milton,2 Daniela Scheurle,1 and Peter L. Lutz2

1Department of Biomedical Sciences, Florida Atlantic University, Boca Raton 33431, and 2Department of Biological Sciences, Florida Atlantic University, Boca Raton, Florida 33431

Submitted 12 May 2003 ; accepted in final form 28 July 2003


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Voltage-dependent potassium channels (Kv channels) are important determinants of brain electrical activity. Hypoxia may be an important modifier, because several voltage-gated K+ channels are reversibly blocked by acute hypoxia and are thought to act as oxygen sensors. Here we show, using the anoxia-tolerant turtle brain (Trachemys scripta) as a model, that brain Kv1 channel transcription is reversibly regulated by oxygen supply. We found that in turtle brains exposed to 4-h anoxia Kv1 transcripts were reduced to 18.5% of normoxic levels. Kv1 channel mRNA levels were restored to normal within 4 h of subsequent reoxygenation. Our results provide clear evidence that brain Kv channel expression is sensitive to oxygen supply and indicate an important mechanism that matches brain activity to oxygen supply.

Trachemys scripta; turtle; anoxia; Kv1 channel

UNABLE TO COMPROMISE on their intense energy consumption, most vertebrate brains go into energy failure within minutes of being deprived of oxygen, resulting in a loss of ionic gradients with consequent depolarization and eventual neuronal death (20a). The freshwater turtle (Trachemys scripta) is one of the few exceptions, having a brain that can survive at least 48 h of anoxia at 25° C (19), allowing it to be described as the archetype of an anoxia-tolerant brain against which less tolerant neural tissues are compared (5).

The most important compensation in the turtle brain for surviving anoxia is, almost uniquely, lowering its energy consumption to "pilot light" levels, where brain energy needs can be fully met by anaerobic glycolysis (6, 9, 21). As a result, the turtle brain is able to maintain ATP levels and ionic gradients during anoxia and thus avoid the fatal consequences of energy failure (19). A reduction in membrane ion leakage (channel arrest) can provide important energy savings for the anoxia-tolerant brain by reducing the costs of ion pumping to maintain homeostasis (11, 12, 20), and several studies indicate that channel arrest is indeed initiated in the anoxic turtle brain. In the anoxic turtle brain, potassium flux is significantly lower than in normoxia (7, 15, 27) and there is a decrease in the density of voltage-gated Na+ channels (28) and a downregulation in NMDA receptor Ca2+ channels (3); these reductions in ion leakage permit a simultaneous decrease in Na+-K+-ATPase activity (14). The mechanisms behind such changes, however, remain elusive.

In the neuron, voltage-dependent K+ (Kv) channels play a critical role in the generation of electrical activity and in modulating neurotransmitter release by opening and closing in response to membrane-potential changes (24, 35). Kv channels are of particular interest in hypoxia studies, as some are sensitive to changes in oxygen supply; acute hypoxia causes the reversible blocking of several voltage-gated K+ channel subunits (including Kv1.2 and Kv1.5 channels) (26). In several tissues, including pulmonary artery smooth muscle (the most studied tissue for this topic), carotid and aortic bodies, and neuroepithelial cells, Kv channels are thought to act as O2 sensors (32, 25). There is some question, however, whether such channels are intrinsically O2 sensitive or are under the control of an "O2 sensor," such as a mitochondrion-located redox O2 sensor (1).

Acute hypoxia may inhibit Kv channel function through a variety of mechanisms that directly affect the protein such as changing redox status and the inhibition of cytochrome P-450 (32). More importantly, as far as channel arrest is concerned, prolonged hypoxia has been shown to inhibit gene expression of Kv channels in pulmonary artery smooth muscle, as evidenced by a significant reduction in the mRNA levels of Kv channel {alpha}-subunits, Kv1.2 and Kv1.5 (33), thereby diminishing the number of Kv channels. In such hypoxia-sensitive cells, changes in Kv channel RNA expression are typically reported after 60-72 h in hypoxia (33). It has also been suggested that the regulation of K+ channel gene expression may be a general mechanism for producing long-term complex changes in excitability during development and learning (16). However, we have no knowledge of the effect of hypoxia on Kv expression in brain despite the importance of the channel on neuronal function. Perhaps surprisingly, during transient focal ischemia, Kv1.2 expression is augmented in some cortical regions of the rat brain (8), which would enhance excitability by decreasing the action potential period. Most ischemia/anoxia-induced changes in the brain, however, are probably pathological, many coinciding with the onset of tissue damage caused, in part, by the release of oxygen free radicals (17).

The aim of this research was to determine whether the turtle reduces Kv channel transcription as part of its long-term anoxia defense strategy of reducing brain metabolic demands. It should be pointed out that, although in the mammal it is often difficult to distinguish between adaptive (functional) and pathological responses to such destructive insults as brain anoxia/ischemia and subsequent reperfusion, the turtle brain responses can be presumed to be adaptive as it survives and fully recovers from many hours of anoxia and subsequent reoxygenation (2, 20a). As the gene responses to hypoxia are highly conserved, the turtle can provide a useful insight into mechanisms behind mammalian failure and survival (13).


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Tissue preparation. Freshwater turtles (Trachemys scripta) obtained from commercial suppliers (W. H. Lemberger, Oshkosh, WI) weighing 300-500 g were individually placed in sealed 2-liter plastic chambers at room temperature (25°C). Three experimental sets of n = 5 included normoxic controls, anoxic animals exposed to 4 h 99.99% N2 (positive pressure flow-through, County Welding, Pompano Beach, FL), and a third group of 4-h anoxia/4-h normoxic recovery. Animals were killed by cervical separation, and the brains were removed into liquid nitrogen in <2 min.

RT-PCR. Total RNA was extracted using the TRIzol reagent (Life Technologies, Grand Island, NY) according to the manufacturer's protocol, and RNA was subjected to treatment with DNase I to eliminate DNA contamination. Complementary DNA was synthesized from total RNA using random hexamers. The PCR reaction using Taq polymerase comprised denaturation for 7 min, 94°C, PCR: 40 cycles (Kv1) or 30 cycles (actin) (1 min, 94°C; 45 s, 55°C; 1.5 min, 72°C) followed by elongation: 10 min, 72°C. For HIF-1, PCR was conducted for 40 cycles (1 min, 94°C; 2 min, 57°C; 3 min, 72°C). The primers employed for PCR reactions were the following: Kv primers: 5'-TGGTTCATYYTVATCTCBATHRTCA-3' (forward) and 5'-ACBACNGCCCACCARAAVGCATC-3' (reverse); actin primers: 5'-CACCAACTGGGACGACATGG-3' (forward) and 5'-GTCGGCCAGCTCGTAGCTCT-3' (reverse); HIF-1{alpha} primers: 5'-TGTGACCATGAGGANNTGAGAGA-3' (forward) and 5'-GNTCNTCTGGNTCATANCCCATCA-3' (reverse). Controls in which RNA or RT were omitted from the RT reaction were carried out to confirm the absence of residual genomic DNA. After electrophoresis of PCR products, gels were stained with ethidium bromide and photographed using a digital camera for quantification using National Institutes of Health Image 1.60 software.

For semiquantitative assessment of Kv1 transcript levels and HIF-1 transcript levels, respectively, RT-PCR signal intensities were expressed as a ratio of levels of PCR products amplified from turtle actin cDNAs.

All experiments were conducted with the approval of Florida Atlantic University Institutional Animal Care and Use Committee.

Statistical analysis. Results are expressed as means ± SE. Statistical significance was evaluated using ANOVA. A value of P < 0.05 was used to denote statistical significance.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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To determine if brain Kv1 channel transcription is influenced by oxygen supply, we measured messenger RNA levels for Kv1 subunits in cerebral tissue from normoxic turtles, turtles subjected to 4-h anoxia, and turtles subjected to 4-h anoxia followed by 4-h normoxic recovery. Levels of mRNA expression were normalized relative to actin mRNA control levels. HIF-1 transcription was also measured.

The anoxic brains showed a substantial downregulation in Kv1 channel transcription to 18.5% of normoxic levels (Fig. 1, A and B). In the recovery set, transcript levels for Kv1 rose 5.6-fold relative to the anoxic brain, returning to original normoxic levels (Fig. 1, A and B). Many studies point to a two-phase response to anoxia in the turtle brain: an initial transitory phase during the first 1 to 2-h anoxia in which there is a coordinated downregulation of energy demanding processes followed by a long-term (h/days) maintenance of the deep hypometabolic state (20a). The purpose of this study was, therefore, to see if a downregulation of Kv was evidenced in the hypometabolic brain and a subsequent restoration of Kv transcription on reoxygenation. No changes were observed for actin or HIF-1 transcripts during anoxia and subsequent recovery, indicating the absence of a generalized transcriptional response to anoxia (Fig. 1, C-E).Go



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  		Fig. 1. Expression levels of Kv1 and HIF-1{alpha} transcripts in the turtle brain. A: quantification of transcription levels for Kv1 gene products expressed as a percentage of actin transcript levels. *P < 0.01 vs. normoxia; **P < 0.01 vs. 4-h anoxia. B: representative Kv1 RT-PCR reaction products; in lane 1, RT was omitted from the Kv1 RT reaction. RTPCR products are shown for Kv1 transcripts from turtle brain under normoxic conditions (lane 2), after 4-h anoxia (lane 3), and after 4-h anoxia/4-h reoxygenation (lane 4). C: quantification of transcription levels for HIF-1{alpha} gene products expressed as a percentage of actin transcript levels. D: representative HIF-1{alpha} RT-PCR reaction products; in lane 1, RT was omitted from the HIF-1{alpha} RT reaction. RT-PCR products are shown for HIF-1{alpha} transcripts from turtle brain under normoxic conditions (lane 2), after 4-h anoxia (lane 3), and after 4-h anoxia/4-h reoxygenation (lane 4). E: representative actin RT-PCR reaction products; in lane 1, RT was omitted from the actin RT reaction. RT-PCR products are shown for actin transcripts from turtle brain under normoxic conditions (lane 2), after 4-h anoxia (lane 3), and after 4-h anoxia/4-h reoxygenation (lane 4).

 

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  		Table 1. Oligonucleotide primer sequences employed for RT-PCR

 


   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
DISCLOSURES
 REFERENCES
 
This is the first report of the regulation of Kv transcription by oxygen supply in neuronal tissue. The downregulation of Kv1 transcripts within 4 h would likely result in a decrease in the corresponding channel protein as Kv channels are known to have a rapid turnover. In rats, for example, Kv1.5 channel protein and mRNA have half-lives of 4 and 0.5 h, respectively (33). In the turtle, a reduction in Kv channel gene expression may be a critical component in the orchestrated reduction in brain energy demand, the key response for brain anoxia survival (29), because it would reduce excitability and ion flux and therefore decrease the cost of ion pumping.

Alterations in Kv channel activity may also have other protective functions in anoxia and recovery. Inhibition of Kv channel expression could contribute to the defense against apoptosis by helping to maintain intracellular K+ concentrations during prolonged anoxia. Physiological levels of potassium inhibit caspase activation by abrogating oligomerization of Apaf-1, a critical process in apoptosome formation (4). More directly, there is evidence in vascular smooth muscle that part of the anti-apoptotic effect mediated by Bcl-2 is due to an inhibition of Kv channel activity (10).

The downregulation of Kv expression could be mediated by hypoxia-related events, either directly through an O2 sensor-initiated process and/or indirectly through hypoxia-enhanced metabolites, neurotransmitters, or growth factors (Fig. 2) (30). In the anoxic turtle brain, for example, the downregulation of ATP-sensitive K+ channels is in part regulated through the activation of adenosine receptors (27). Antiapoptotic components such as Bcl-2 may also play a role in regulating Kv channel transcription (4). In the turtle, Bcl-2 mRNA levels are increased in the anoxic brain with maximal levels of expression observed at 6 h of anoxia in hindbrain and forebrain (22). In the mitochondria, the in situ oxygen affinity of cytochrome aa3 is lower in the turtle brain compared with the rat (31), suggesting that mitochondrial redox changes may occur earlier and thus be detected by the hypoxic turtle brain sooner than in mammals.



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  		Fig. 2. Regulation of voltage-gated potassium channel gene transcription. Downregulation of Kv expression may be mediated directly through an O2 sensor-initiated process and/or through indirect processes, including enhanced metabolites or neurotransmitters. Potential signals for upregulation of Kv transcription include activated O2 sensors, release of reactive oxygen species (ROS), and/or changes in mitochondrial redox status. -ve, signals for downregulating Kv transcription; +ve, signals for upregulating Kv transcription.

 

Potential signals or mediators for the upregulation of Kv transcription when oxygen supply is restored include activated O2 sensors, release of reactive oxygen species (ROS) and/or changes in mitochondrial redox status (34, 18). We previously found mRNA expression in turtle brain for the hypoxia sensor and transcriptional regulator HIF-1{alpha} (22). In the turtle brain, switching from normoxia to anoxia produced changes in a DNA binding activity that is specific to an HIF-1 promoter consensus site and in levels of the redox-regulated transcription factor NF-{kappa}B (22). In addition to its remarkable ability to survive anoxia, the turtle brain has an exceptional capacity to tolerate a massive increase in ROS on reoxygenation. The turtle has enhanced mechanisms that protect against the formation of ROS and mechanisms to protect against the damaging effects of ROS (23).

In conclusion, our observations of a decrease in turtle brain Kv1 mRNA in anoxia and a subsequent increase on reoxygenation demonstrate that brain Kv channel expression is sensitive to oxygen supply, either directly or indirectly, and indicate an important mechanism that matches brain activity to oxygen availability.


   DISCLOSURES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
REFERENCES
 
This work was supported by the Florida Atlantic University Foundation and the American Heart Association (Florida Affiliate).


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. M. Prentice, Dept. of Biomedical Sciences, Florida Atlantic Univ., 777 Glades Rd., Boca Raton, FL 33431 (E-mail: hprentic{at}fau.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 MATERIALS AND METHODS
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