Transgenic expression of human equilibrative nucleoside transporter 1 in mouse neurons

Parkinson, Fiona E.; Xiong, Wei; Zamzow, Christina R.; Chestley, Taeyo; Mizuno, Tooru M.; Duckworth, Mary Lynn

doi:10.1111/j.1471-4159.2009.05991.x

Cited by 29 publications

(40 citation statements)

References 35 publications

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“…Here we have used a molecular approach based on quantitative real-time RT-PCR, and our findings correlate with previous studies (7,8,17). Moreover, description of an ENT1 overexpressing transgenic model reported no compensatory effects in the expression of adenosine receptors, other nucleoside transporter isoforms, or purine metabolizing enzymes (38).…”

Section: Discussionsupporting

confidence: 83%

Equilibrative nucleoside transporter 1 plays an essential role in cardioprotection

Rose

Naydenova²,

Bang³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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To better understand the role of equilibrative nucleoside transporters (ENT) in purine nucleoside-dependent physiology of the cardiovascular system, we investigated whether the ENT1-null mouse heart was cardioprotected in response to ischemia (coronary occlusion for 30 min followed by reperfusion for 2 h). We observed that ENT1-null mouse hearts showed significantly less myocardial infarction compared with wild-type littermates. We confirmed that isolated wild-type adult mouse cardiomyocytes express predominantly ENT1, which is primarily responsible for purine nucleoside uptake in these cells. However, ENT1-null cardiomyocytes exhibit severely impaired nucleoside transport and lack ENT1 transcript and protein expression. Adenosine receptor expression profiles and expression levels of ENT2, ENT3, and ENT4 were similar in cardiomyocytes isolated from ENT1-null adult mice compared with cardiomyocytes isolated from wild-type littermates. Moreover, small interfering RNA knockdown of ENT1 in the cardiomyocyte cell line, HL-1, mimics findings in ENT1-null cardiomyocytes. Taken together, our data demonstrate that ENT1 plays an essential role in cardioprotection, most likely due to its effects in modulating purine nucleoside-dependent signaling and that the ENT1-null mouse is a powerful model system for the study of the role of ENTs in the physiology of the cardiomyocyte.

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Section: Discussionsupporting

confidence: 83%

Equilibrative nucleoside transporter 1 plays an essential role in cardioprotection

Rose

Naydenova²,

Bang³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…68 On the other hand, transgenic overexpression of human ENT1 in mouse neurons increases sensitivity to the acute intoxicating effects of alcohol. 69 In summary, the ENT1-dependent increase in the extracellular concentration of adenosine, by acting on A 1 receptors localized in different brain areas, seems to play a very important role in the ataxic, somnogenic, and anxiolytic effects of the acute administration of alcohol. Does adenosine also play any role in the reinforcing effects of alcohol?…”

Section: Ferré and O'brienmentioning

confidence: 99%

“…In fact, chronic alcohol exposure results in a decreased expression of ENT1 and, therefore, a decrease in alcohol-mediated inhibition of ENT1. 69 The loss of reuptake of adenosine after chronic exposure to alcohol is most probably the main mechanism by which alcohol tolerance develops both in cell lines 69 and animals. 72 Several studies have shown that the consequent reduction in the adenosine tone is associated with an upregulation of A 1 receptors, which seems to be at least partially responsible for the tolerance to the acute effects of alcohol and also to the main symptoms of alcohol withdrawal, such as insomnia, anxiety, and seizures (Fig.…”

Section: Adenosine Mechanisms In the Chronic Pharmacological Effects mentioning

confidence: 99%

Alcohol and Caffeine: The Perfect Storm

Ferré

O’Brien

2011

Journal of Caffeine Research

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Although it is widely believed that caffeine antagonizes the intoxicating effects of alcohol, the molecular mechanisms underlying their interaction are incompletely understood. It is known that both caffeine and alcohol alter adenosine neurotransmission, but the relationship is complex, and may be dose dependent. In this article, we review the available literature on combining caffeine and alcohol. Ethical constraints prohibit laboratory studies that would mimic the high levels of alcohol intoxication achieved by many young people in real-world settings, with or without the addition of caffeine. We propose a possible neurochemical mechanism for the increase in alcohol consumption and alcohol-related consequences that have been observed in persons who simultaneously consume caffeine. Caffeine is a nonselective adenosine receptor antagonist. During acute alcohol intake, caffeine antagonizes the "unwanted" effects of alcohol by blocking the adenosine A receptors that mediate alcohol's somnogenic and ataxic effects. The A receptor-mediated "unwanted" anxiogenic effects of caffeine may be ameliorated by alcohol-induced increase in the extracellular concentration of adenosine. Moreover, by means of interactions between adenosine A and dopamine D receptors, caffeine-mediated blockade of adenosine A receptors can potentiate the effects of alcohol-induced dopamine release. Chronic alcohol intake decreases adenosine tone. Caffeine may provide a "treatment" for the withdrawal effects of alcohol by blocking the effects of upregulated A receptors. Finally, blockade of A receptors by caffeine may contribute to the reinforcing effects of alcohol.

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“…Given that during excitotoxic conditions, adenosine appears to be released selectively from neurons via a nucleoside transporter mechanism, we developed a transgenic mouse model to further explore adenosine release mechanisms [23] . A transgene consisting of the rat promoter region for neuron specific enolase was coupled to the coding sequence of human equilibrative nucleoside transporter 1 (hENT1) and used to develop mice with neuron specific expression of hENT1.…”

Section: Cultured Neurons But Not Astrocytes Release Adenosine Via mentioning

confidence: 99%

“…We reasoned that ENT facilitate adenosine efflux during events where adenosine receptor mediated effects are a result of intracellular adenosine formation, subsequent to ATP utilization, yet facilitate adenosine influx during events where adenosine receptor mediated effects are a result of extracellular adenosine formation ( Figure 2). Since neurons are more sensitive to ischemic injury than astrocytes and show more rapid depletion of intracellular ATP [20] , and since in cell culture rat neurons appear to release adenosine per se during stroke-like conditions [22] , we created mice with neuron specific expression of hENT1 [23] .…”

Section: Cultured Neurons But Not Astrocytes Release Adenosine Via mentioning

confidence: 99%

Regulation of adenosine levels during cerebral ischemia

et al. 2012

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Adenosine is a neuromodulator with its level increasing up to 100-fold during ischemic events, and attenuates the excitotoxic neuronal injury. Adenosine is produced both intracellularly and extracellularly, and nucleoside transport proteins transfer adenosine across plasma membranes. Adenosine levels and receptor-mediated effects of adenosine are regulated by intracellular ATP consumption, cellular release of ATP, metabolism of extracellular ATP (and other adenine nucleotides), adenosine influx, adenosine efflux and adenosine metabolism. Recent studies have used genetically modified mice to investigate the relative contributions of intra-and extracellular pathways for adenosine formation. The importance of cortical or hippocampal neurons as a source or a sink of adenosine under basal and hypoxic/ischemic conditions was addressed through the use of transgenic mice expressing human equilibrative nucleoside transporter 1 (hENT1) under the control of a promoter for neuron-specific enolase. From these studies, we conclude that ATP consumption within neurons is the primary source of adenosine in neuronal cultures, but not in hippocampal slices or in vivo mice exposed to ischemic conditions.

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Transgenic expression of human equilibrative nucleoside transporter 1 in mouse neurons

Cited by 29 publications

References 35 publications

Equilibrative nucleoside transporter 1 plays an essential role in cardioprotection

Equilibrative nucleoside transporter 1 plays an essential role in cardioprotection

Alcohol and Caffeine: The Perfect Storm

Regulation of adenosine levels during cerebral ischemia

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