Expression of human equilibrative nucleoside transporter 1 in mouse neurons regulates adenosine levels in physiological and hypoxic‐ischemic conditions
- 6 April 2011
- journal article
- Published by Wiley in Journal of Neurochemistry
- Vol. 118 (1), 4-11
- https://doi.org/10.1111/j.1471-4159.2011.07242.x
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.Keywords
This publication has 30 references indexed in Scilit:
- Altered glutamatergic neurotransmission in the striatum regulates ethanol sensitivity and intake in mice lacking ENT1Behavioural Brain Research, 2010
- C-Jun N-terminal kinase regulates adenosine A1 receptor-mediated synaptic depression in the rat hippocampusNeuropharmacology, 2007
- Nucleoside transporters: from scavengers to novel therapeutic targetsTrends in Pharmacological Sciences, 2006
- Adenosine and Brain FunctionInternational Review of Neurobiology, 2005
- The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preferenceNature Neuroscience, 2004
- Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cellsBiochemical Pharmacology, 2001
- Direct measurement of adenosine release during hypoxia in the CA1 region of the rat hippocampal sliceThe Journal of Physiology, 2000
- Adenosine analogs mediating depressant effects on synaptic transmission in rat hippocampus: Structure-activity relationships for the N6 subregionNaunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie, 1986
- Adenosine increases synaptic facilitation in the in vitro rat hippocampus: evidence for a presynaptic site of action.The Journal of Physiology, 1985
- Interactions between the effects of adenosine and calcium on synaptic responses in rat hippocampus in vitro.The Journal of Physiology, 1984