Abstract
To assess the putative role of adenosine triphosphate (ATP) upon nitric oxide (NO) production in the hippocampus, we used as a model both rat hippocampal slices and isolated hippocampal neurons in culture, lacking glial cells. In hippocampal slices, additions of exogenous ATP or 2′(3′)-O-(4-Benzoylbenzoyl) ATP (Bz-ATP) elicited concentration-dependent NO production, which increased linearly within the first 15 min and plateaued thereafter; agonist EC50 values were 50 and 15 µM, respectively. The NO increase evoked by ATP was antagonized in a concentration-dependent manner by Coomassie brilliant blue G (BBG) or by Nω-propyl-L-arginine, suggesting the involvement of P2X7Rs and neuronal NOS, respectively. The ATP induced NO production was independent of N-methyl-D-aspartic acid (NMDA) receptor activity as effects were not alleviated by DL-2-Amino-5-phosphonopentanoic acid (APV), but antagonized by BBG. In sum, exogenous ATP elicited NO production in hippocampal neurons independently of NMDA receptor activity.
Highlights
Nitric oxide (NO) and adenosine triphosphate (ATP) are ubiquitous extracellular messengers involved in multiple physiological and pathophysiological processes in the nervous system and peripheral tissues [1]
NO is produced by L-arginine oxidation, a reaction catalyzed by the nitric oxide synthase (NOS) family. nNOS and eNOS are the constitutive enzyme isoforms found predominantly in neurons and endothelial cells, respectively; these two proteins are controlled by Ca+2-calmodulin (CaM) in a concentration-dependent manner
Released ATP acts on ionotropic receptors (P2XRs) or metabotropic receptors (P2YRs), and both classes of purinoceptors are widely distributed in the brain nuclei and peripheral tissues [11]
Summary
Nitric oxide (NO) and ATP are ubiquitous extracellular messengers involved in multiple physiological and pathophysiological processes in the nervous system and peripheral tissues [1]. Given that ATP and its receptors are involved in brain excitability and in long-term potentiation (LTP) [16], studies of this functional link are highly relevant, in the hippocampus. Trace metals such as 1–10 mM zinc have been shown to increase the magnitude of the ATP component of hippocampal LTP [16]. We deemed relevant to ascertain whether nucleotides and purinoceptors are involved as regulators of brain excitability In this communication, we demonstrate, for the first time, that in rat hippocampus slices, as in isolated hippocampus neurons, the application of exogenous ATP increases NO production through P2X7R activation. Since the increase in NO production is resistant to APV, a classical NMDARs antagonist, we conclude that this effect is independent of glutamate NMDARs activation
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