Mechanism and function of excitatory amino acid-evoked adenosine release from rat parietal cortex.
Date
1992
Authors
Craig, Constance Grace.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
Excitatory amino acids (EAAs) such as glutamate and aspartate are the major excitatory neutransmitters in the cerebral cortex. EEAs, acting at both NMDA and non-NMDA receptors, release the inhibitory neuromodulator adenosine from superfused cortical slices. Results with Mg$\sp{2+}$, MK-801 and 7-chlorokynurenic acid, which are non-competitive NMDA antagonists, indicate that there may be spare receptors for NMDA-evoked adenosine release, possibly contributing to the previously observed 33-fold increased potency of NMDA at releasing adenosine vs. ($\sp3$H) noradrenaline. Endogenous glycine, acting at a strychnine-insensitive glycine binding site on the NMDA receptor, is required for NMDA receptor mediated release of adenosine and ($\sp3$H) noradrenaline. However, heterogeneous glycine concentrations within the cortical slices cannot account for the observed spare receptor phenomenon for NMDA-evoked adenosine release. Pretreatment of slices with a concentration of NMDA (10 $\mu$M) which releases substantial adenosine but very little ($\sp3$H) noradrenaline decreased subsequent 100 $\mu$M NMDA-evoked ($\sp3$H) noradrenaline release. 8-Phenyltheophylline partially reversed this inhibition but had no effect on ($\sp3$H) noradrenaline release evoked by 100 $\mu$M NMDA alone. This indicates that adenosine, released during submaximal NMDA receptor activation, may provide a purinergic inhibitory threshold which must be overcome in order for other NMDA-mediated processes to proceed maximally. Studies characterizing the nature of the purines released during EAA receptor stimulation indicate that activation of non-NMDA receptors releases adenosine per se in a Ca$\sp{2+}$-independent manner. In contrast, NMDA receptor activation releases a nucleotide which is subsequently converted extracellulary to adenosine; in this case, release is Ca$\sp{2+}$-dependent. Although neither NMDA- nor non-NMDA-evoked adenosine release occurs via the DPR-nucleoside transporter, this transporter does appear to be a major route for removal of this adenosine from the extracellular space. IBMX, a non-selective phosphodiesterase inhibitor, blocked NMDA- but not kainate- nor AMPA-evoked adenosine release. This inhibition was not accompanied by enhanced cAMP recovery, probenecid did not block the nucleotide release and forskolin slightly increased NMDA-evoked release. These findings suggest that cAMP may be degraded intracellularly to 5$\sp\prime$AMP which is then released and converted to adenosine by ecto-5$\sp\prime$-nucleotidase. Results with more selective PDE inhibitors indicate that IBMX may exert its effects independent of PDE inhibition. NMDA-evoked adenosine release is not mediated by NO production, calmodulin, arachidonic acid release or intracellular Ca$\sp{2+}$ release, all of which have been shown to be required for NMDA-dependent long-term potentiation in the hippocampus.
Thesis (Ph.D.)--Dalhousie University (Canada), 1992.
Thesis (Ph.D.)--Dalhousie University (Canada), 1992.
Keywords
Biology, Neuroscience., Chemistry, Biochemistry.