Presynaptic Release-regulating Metabotropic Glutamate Receptors: An Update

Abstract

Metabotropic glutamate (mGlu) receptors represent the largest family of glutamate receptors in mammals and act as fine tuners of the chemical transmission in central nervous system (CNS). In the last decade, results concerning the expression and the subcellular localization of mGlu receptors further clarified their role in physio-pathological conditions. Concomitantly, their pharmacological characterization largely improved thanks to the identification of new compounds (chemical ligands and antibodies recognizing epitopic sequences of the receptor proteins) that allowed to decipher the protein compositions of the naive receptors. mGlu receptors are expressed at the presynaptic site of chemical synapses. Here, they modulate intraterminal enzymatic pathways controlling the migration and the fusion of vesicles to synaptic membranes as well as the phosphorylation of colocalized receptors. Both the control of transmitter exocytosis and the phosphorylation of colocalized receptors elicited by mGlu receptors are relevant events that dictate the plasticity of nerve terminals, and account for the main role of presynaptic mGlu receptors as modulators of neuronal signalling. The role of the presynaptic mGlu receptors in the CNS has been the matter of several studies and this review aims at briefly summarizing the recent observations obtained with isolated nerve endings (we refer to as synaptosomes). We focus on the pharmacological characterization of these receptors and on their receptor-receptor interaction / oligo-dimerization in nerve endings that could be relevant to the development of new therapeutic approaches for the cure of central pathologies.

Keywords: Synaptosomes; mGlu1/5; mGlu2/3; mGlu7; oligomerization; presynaptic receptors; receptor-receptor interaction; transmitter release.

Fig. (1)

Correlation between agonist-receptor interaction and release efficiency in superfused synaptosomes. Synaptosomes are endowed with several receptor subtypes (i.e. AR and BR) that may colocalize in the same particles and that, once activated by selected ligands (i.e. AL and BL), might control the transmitter release. A) AR and BR exist on different synaptosomes or coexist in the same particles where they control transmitter exocytosis when activated by the respective agonists AL and BL independently one from each other. The concomitant activation of the two receptors would lead to a releasing activity corresponding to the sum of the releasing activity elicited by each receptor. B) AR and BR are functionally coupled and control transmitter exocytosis. The binding of AL to AR controls the release of the transmitter but also activates transducing pathways that reverberate on the colocalized BR influencing the releasing activity elicited by BL, either potentiating it (B, right) or decreasing it (B, left). C) AL acting at AR does not modify per se the transmitter release but affects the releasing activity elicited by BL acting at BR, either potentiating (C, left) or reducing (C, right) it. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

The contribution of the group I mGlu receptors to the presynaptic control of transmitter release from synaptosomes. A. mGlu1 and mGlu5 homodimeric receptors colocalize in mouse cortical glutamatergic nerve endings, but respond differently to the orthosteric agonists, representing respectively the low and the high affinity receptors. The two receptors do not modify the spontaneous release of glutamate but potentiate the depolarization-evoked glutamate exocytosis. B. mGlu1 receptors are present in cerebellar glutamatergic nerve endings, but the data so far available does not allow to predict whether the receptors exist in monomeric or dimeric assembly. The mGlu1 receptor does not affect the spontaneous release of glutamate but reinforces the depolarization-evoked glutamate exocytosis. C. mGlu1 and mGlu5 autoreceptors exist and colocalize in spinal cord synaptosomes, where they functionally associate to release glutamate. The two receptors increase the spontaneous release of glutamate. D. mGlu1/ mGlu5 containing receptors exist in human cortical cholinergic terminals where their activation elicits the release of acetylcholine. The two receptors compensate one each other, since the blockade of the 3,5-DHPG-evoked releasing activity is achieved only when the mGlu1 and the mGlu5 receptor antagonists are concomitantly added. The very low percentage of the cholinergic synaptosomes did not allow to perform immunocytochemical analysis to investigate the receptor protein assembly but the functional results seems best interpreted by assuming the colocalization of mGlu1 and mGlu5 homodimeric receptors. E. mGlu1 and mGlu5 receptors also exist in hippocampal noradrenergic terminals and cooperate in an exclusive manner. The receptors do not modify on their own the spontaneous release of the amine but potentiate the NMDA-mediated releasing activity. We propose that homodimeric mGlu1 and mGlu5 heteroreceptors colocalize in these terminals to modulate the releasing activity elicited by the activation of colocalized NMDA receptors. (A higher resolution / colour version of this figure is available in the electronic copy of the article).