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 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.

Acute Low Dose of Trazodone Recovers Glutamate Release Efficiency and mGlu2/3 Autoreceptor Impairments in the Spinal Cord of Rats Suffering From Chronic Sciatic Ligation

“…Among glutamate receptors, the mGlu belonging to the group II function as inhibitory release-regulating autoreceptors in the CNS of mammals, including the spinal cord ( Gerber et al., 2000 ; Di Prisco et al., 2012 ; Di Prisco et al., 2016 ). These receptors preferentially locate nearby the site of transmitter exocytosis and are activated by glutamate exceeding the physiological level and diffusing beyond the synaptic active zone ( Olivero et al., 2019 ; Pittaluga, 2019 ).…”

“…Besides genetic and epigenetic mechanisms of control of the mGlu2/3 receptors expression ( Chiechio et al., 2009 ), we recently demonstrated that their insertion in synaptosomal plasmamembranes as well as their releasing activity is controlled by mechanisms of “metamodulation” ( Olivero et al., 2019 ). The term “metamodulation” refers to the mechanism(s) of control of synaptic plasticity based on the functional crosstalk linking two receptors colocalized on the same nerve endings ( Sebastião and Ribeiro, 2015 ).…”

Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System

“…The term "metamodulation" [39,75,76] was first proposed to recapitulate the physical and functional integration of colocalized GPCRs [72][73][74][75], with particular emphasis to their impact on the efficiency of neurotransmitter release, but it is now extended also to the receptor-receptor interactions involving ionotropic receptors [77,78] or transporters [58].…”

“…The functional interaction is referred to as an "agonist-like interaction" when the final effect is higher than the sum of the receptor-induced events (i.e., the mGlu1-mGlu5 receptors [76] or the nACh-NMDA receptors interactions [58]), or, conversely, it is defined an "antagonist-like interaction" if the outcome is quantitatively lower (i.e., the mGlu2/3 and the 5-HT 2A receptors [79]).…”

Antibodies Against the NH2-Terminus of the GluA Subunits Affect the AMPA-Evoked Releasing Activity: The Role of Complement

“…Functional adaptations induced by antibodies recognizing the N-terminal of membrane receptors subunits also could be detected in isolated nerve endings (we refer to as synaptosomes). In particular, commercially available antibodies recognizing the NH2-sequence of receptor subunits affect the receptor-mediated control of transmitter exocytosis from these particles and can be used as pharmacological tools for the characterization of the subunit composition of metabotropic (22)(23)(24)(25) and ionotropic (26) receptors in synaptosomes isolated from different CNS regions ("the immunopharmacological approach") (23,26).…”