Expression of human equilibrative nucleoside transporter 1 in mouse neurons regulates adenosine levels in physiological and hypoxic-ischemic conditions.
Identifieur interne : 001674 ( Main/Exploration ); précédent : 001673; suivant : 001675Expression of human equilibrative nucleoside transporter 1 in mouse neurons regulates adenosine levels in physiological and hypoxic-ischemic conditions.
Auteurs : Dali Zhang [Canada] ; Wei Xiong ; Benedict C. Albensi ; Fiona E. ParkinsonSource :
- Journal of neurochemistry [ 1471-4159 ] ; 2011.
English descriptors
- KwdEn :
- Action Potentials (drug effects), Action Potentials (physiology), Adenosine (analogs & derivatives), Adenosine (metabolism), Adenosine (pharmacology), Adenosine A1 Receptor Antagonists (pharmacology), Animals, Dose-Response Relationship, Drug, Equilibrative Nucleoside Transporter 1 (genetics), Equilibrative Nucleoside Transporter 1 (metabolism), Female, Glucose (deficiency), Glutathione (analogs & derivatives), Glutathione (pharmacology), Hippocampus (pathology), Humans, Hypoxia (pathology), In Vitro Techniques, Mice, Mice, Transgenic, Neurons (drug effects), Neurons (physiology), Patch-Clamp Techniques, Protein Binding (drug effects), Protein Binding (physiology), Purinergic P1 Receptor Agonists (pharmacology), Statistics, Nonparametric, Synaptic Transmission (drug effects), Synaptic Transmission (genetics), Thioinosine (analogs & derivatives), Thioinosine (pharmacokinetics), Tritium (pharmacokinetics), Xanthines (pharmacology).
- MESH :
- chemical , analogs & derivatives : Adenosine, Glutathione, Thioinosine.
- chemical , deficiency : Glucose.
- drug effects : Action Potentials, Neurons, Protein Binding, Synaptic Transmission.
- chemical , genetics : Equilibrative Nucleoside Transporter 1, Synaptic Transmission.
- chemical , metabolism : Adenosine, Equilibrative Nucleoside Transporter 1.
- pathology : Hippocampus, Hypoxia.
- chemical , pharmacokinetics : Thioinosine, Tritium.
- chemical , pharmacology : Adenosine, Adenosine A1 Receptor Antagonists, Glutathione, Purinergic P1 Receptor Agonists, Xanthines.
- physiology : Action Potentials, Neurons, Protein Binding.
- Animals, Dose-Response Relationship, Drug, Female, Humans, In Vitro Techniques, Mice, Mice, Transgenic, Patch-Clamp Techniques, Statistics, Nonparametric.
Abstract
Activation of adenosine A(1) receptors inhibits excitatory synaptic transmission. Equilibrative nucleoside transporters (ENTs) regulate extracellular adenosine levels; however, the role of neuronal ENTs in adenosine influx and efflux during cerebral ischemia has not been determined. We used mice with neuronal expression of human ENT type 1 and wild type (Wt) littermates to compare responses to in vitro hypoxic or ischemic conditions. Extracellular recordings in the CA1 region of hippocampal slices from transgenic (Tg) mice revealed increased basal synaptic transmission, relative to Wt slices, and an absence of 8-cyclopentyl-1,3-dipropyl-xanthine mediated augmentation of excitatory neurotransmission. Adenosine (10-100 μM) had a reduced potency for inhibiting synaptic transmission in slices from Tg mice; inhibitory concentration 50% values were approximately 25 and 50 μM in Wt and Tg slices, respectively. Potency of the A(1) receptor agonist N(6) -cyclopentyladenosine (1 nM-1 μM) was unchanged. Transient hypoxia or oxygen-glucose deprivation produced greater inhibition of excitatory neurotransmission in slices from Wt than Tg, mice. The ENT1 inhibitor S-(4-nitrobenzyl)-6-thioinosine abolished these differences. Taken together, our data provide evidence that neuronal ENTs reduce hypoxia- and ischemia-induced increases in extracellular adenosine levels and suggest that inhibition of neuronal adenosine transporters may be a target for the treatment of cerebral ischemia.
DOI: 10.1111/j.1471-4159.2011.07242.x
PubMed: 21395582
Affiliations:
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Albensi</name></author><author><name sortKey="Parkinson, Fiona E" sort="Parkinson, Fiona E" uniqKey="Parkinson F" first="Fiona E" last="Parkinson">Fiona E. Parkinson</name></author></analytic><series><title level="j">Journal of neurochemistry</title><idno type="eISSN">1471-4159</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Action Potentials (drug effects)</term><term>Action Potentials (physiology)</term><term>Adenosine (analogs & derivatives)</term><term>Adenosine (metabolism)</term><term>Adenosine (pharmacology)</term><term>Adenosine A1 Receptor Antagonists (pharmacology)</term><term>Animals</term><term>Dose-Response Relationship, Drug</term><term>Equilibrative Nucleoside Transporter 1 (genetics)</term><term>Equilibrative Nucleoside Transporter 1 (metabolism)</term><term>Female</term><term>Glucose (deficiency)</term><term>Glutathione (analogs & derivatives)</term><term>Glutathione (pharmacology)</term><term>Hippocampus (pathology)</term><term>Humans</term><term>Hypoxia (pathology)</term><term>In Vitro Techniques</term><term>Mice</term><term>Mice, Transgenic</term><term>Neurons (drug effects)</term><term>Neurons (physiology)</term><term>Patch-Clamp Techniques</term><term>Protein Binding (drug effects)</term><term>Protein Binding (physiology)</term><term>Purinergic P1 Receptor Agonists (pharmacology)</term><term>Statistics, Nonparametric</term><term>Synaptic Transmission (drug effects)</term><term>Synaptic Transmission (genetics)</term><term>Thioinosine (analogs & derivatives)</term><term>Thioinosine (pharmacokinetics)</term><term>Tritium (pharmacokinetics)</term><term>Xanthines (pharmacology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Adenosine</term><term>Glutathione</term><term>Thioinosine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Glucose</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Action Potentials</term><term>Neurons</term><term>Protein Binding</term><term>Synaptic Transmission</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Equilibrative Nucleoside Transporter 1</term><term>Synaptic Transmission</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adenosine</term><term>Equilibrative Nucleoside Transporter 1</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Hippocampus</term><term>Hypoxia</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Thioinosine</term><term>Tritium</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Adenosine</term><term>Adenosine A1 Receptor Antagonists</term><term>Glutathione</term><term>Purinergic P1 Receptor Agonists</term><term>Xanthines</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Action Potentials</term><term>Neurons</term><term>Protein Binding</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Dose-Response Relationship, Drug</term><term>Female</term><term>Humans</term><term>In Vitro Techniques</term><term>Mice</term><term>Mice, Transgenic</term><term>Patch-Clamp Techniques</term><term>Statistics, Nonparametric</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Activation of adenosine A(1) receptors inhibits excitatory synaptic transmission. Equilibrative nucleoside transporters (ENTs) regulate extracellular adenosine levels; however, the role of neuronal ENTs in adenosine influx and efflux during cerebral ischemia has not been determined. We used mice with neuronal expression of human ENT type 1 and wild type (Wt) littermates to compare responses to in vitro hypoxic or ischemic conditions. Extracellular recordings in the CA1 region of hippocampal slices from transgenic (Tg) mice revealed increased basal synaptic transmission, relative to Wt slices, and an absence of 8-cyclopentyl-1,3-dipropyl-xanthine mediated augmentation of excitatory neurotransmission. Adenosine (10-100 μM) had a reduced potency for inhibiting synaptic transmission in slices from Tg mice; inhibitory concentration 50% values were approximately 25 and 50 μM in Wt and Tg slices, respectively. Potency of the A(1) receptor agonist N(6) -cyclopentyladenosine (1 nM-1 μM) was unchanged. Transient hypoxia or oxygen-glucose deprivation produced greater inhibition of excitatory neurotransmission in slices from Wt than Tg, mice. The ENT1 inhibitor S-(4-nitrobenzyl)-6-thioinosine abolished these differences. Taken together, our data provide evidence that neuronal ENTs reduce hypoxia- and ischemia-induced increases in extracellular adenosine levels and suggest that inhibition of neuronal adenosine transporters may be a target for the treatment of cerebral ischemia.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Manitoba</li></region><settlement><li>Winnipeg</li></settlement><orgName><li>Université du Manitoba</li></orgName></list><tree><noCountry><name sortKey="Albensi, Benedict C" sort="Albensi, Benedict C" uniqKey="Albensi B" first="Benedict C" last="Albensi">Benedict C. Albensi</name><name sortKey="Parkinson, Fiona E" sort="Parkinson, Fiona E" uniqKey="Parkinson F" first="Fiona E" last="Parkinson">Fiona E. Parkinson</name><name sortKey="Xiong, Wei" sort="Xiong, Wei" uniqKey="Xiong W" first="Wei" last="Xiong">Wei Xiong</name></noCountry><country name="Canada"><region name="Manitoba"><name sortKey="Zhang, Dali" sort="Zhang, Dali" uniqKey="Zhang D" first="Dali" last="Zhang">Dali Zhang</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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