Presynaptic release-regulating NMDA receptors in isolated nerve terminals: A narrative review

Abstract

The existence of presynaptic, release-regulating NMDA receptors in the CNS has been long matter of discussion. Most of the reviews dedicated to support this conclusion have preferentially focussed on the results from electrophysiological studies, paying little or no attention to the data obtained with purified synaptosomes, even though this experimental approach has been recognized as providing reliable information concerning the presence and the role of presynaptic release-regulating receptors in the CNS. To fill the gap, this review is dedicated to summarising the results from studies with synaptosomes published during the last 40 years, which support the existence of auto and hetero NMDA receptors controlling the release of transmitters such as glutamate, GABA, dopamine, noradrenaline, 5-HT, acetylcholine and peptides, in the CNS of mammals. The review also deals with the results from immunochemical studies in isolated nerve endings that confirm the functional observations.

Keywords: GluN subunit; glutamate; glycine; presynaptic NMDA receptor; synaptosomes; transmitter release.

FIGURE 1

The up‐down superfusion of a thin layer of synaptosomes as first proposed by Maurizio Raiteri and colleagues in 1974. (a) The continuous flowing of the superfusion medium assures the quick removal of any endogenous substance released by the superfused particles, then minimizing the shortcomings due to the presence of the biophase (which has major effects on electrophysiological recordings in slices). (b) In this dynamic condition, presynaptic release‐regulating receptors are activated by receptor ligands exogenously added to the superfusion medium. By acting at the respective binding sites (e.g., on the respective GluN subunits), the orthosteric agonists added to the superfusion medium (e.g., glutamate and glycine for the NMDA receptors) influence the molecular events controlling vesicular exocytosis, then causing significant changes to transmitter overflow that could be quantified and correlated with the activation of the presynaptic receptors. Notably, the technique also permits distinguishing between the spontaneous and the depolarization‐evoked release of a selected transmitter, a discrimination that cannot be easily achieved in electrophysiological studies (see for technical information Raiteri & Raiteri, 2000)

FIGURE 2

Heterogeneity of the presynaptic release‐regulating NMDA receptors. The pharmacological profile of the receptors was obtained using selective ligands for the GluN subunits, as well as compounds acting at the voltage dependent associated channel. The results are consistent with the presence of (a) dimeric GluN1/GluN2B assemblies in the dopaminergic and the noradrenergic nerve endings and of heteromeric GluN associations typified by a high level of complexity in (b) peptidergic and (c) glutamatergic terminals. The NMDA receptors also act differently on the transmitter outflow. (a and c) Presynaptic NMDA receptors controlling dopamine, noradrenaline and glutamate potentiate the spontaneous release of these transmitters, whereas (b) the presynaptic NMDA receptors controlling the release of CCK‐LI and SRIF‐LI significantly reinforce the exocytosis of the two peptides elicited by a mild depolarizing stimulus. Straight line with arrow: full agonist; dotted line with arrow: partial agonist; straight line with cap: antagonist/channel blockers; dotted line with breaks: antagonist/channel blockers inactive at the receptor