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  • However no reviews was focused

    2021-09-11

    However, no reviews was focused on all the glutamate heteroreceptor complexes and how to understand why some were formed and not others in the glutamate synapses and their extrasynaptic regions. These receptor complexes are present on the glutamate nerve terminals and the dendritic spines on which the glutamate synapse is located (Fig. 1). Thus, there is a gap in our knowledge to understand why certain mGluR, NMDAR, and AMPAR heteroreceptor complexes can form heteromers while others fail to do so (see www.gpcr-hetnet.com [7,[12], [13], [14]]). Our perspective is that the formation of glutamate receptor heteromers is linked to the existence of triplet amino dna synthesis homologies (protriplets) in a putative receptor interface domain [15,16]. Using a mathematical approach, this triplet puzzle theory states that these protriplets represent one general molecular mechanism to help develop heteroreceptor complexes and their receptor–receptor interactions by guiding them towards each other [[15], [16], [17]]. We have tested this theory in the current review on glutamate heteroreceptor complexes.
    Conclusions and remarks Convincing evidence was also obtained that D1R, D2R and MOR can form heteroreceptor complexes with NMDARs via GluN1, GluN2A and/or GluN2 B subunits. In the case of AMPA receptors clear-cut evidence for the existence of a heteroreceptor complex only exists for the interaction between IFNgR1 and the AMPAR mediated via the subunit GluA1.
    Conflict of interest
    Acknowledgements The authors are supported by grants from the Swedish Medical Research Council (04×-715 and VR-link) to K.F., by Hjärnfonden (FO2016-0302) to D.O.B-E and by AFA Försäkring (130328) to K.F. and D.O.B-E. D.O.B-E belongs to Academia de Biólogos Cubanos. A.O.T. has not received any support for this work. It is with deep sadness we must report that Dr. Alexander O. Tarakanov died in the beginning of this year. He played a highly significant role in introducing the triplet puzzle theory which states that triplet amino acid homologies play a major role in protein–protein interactions taking place e.g., in the interface of receptor heterodimers.
    Introduction
    Glutamate Glu is present in high concentrations in practically all of the brain areas and its receptors are widely distributed and expressed in neuronal and non-neuronal cells. This excitatory amino acid plays an important role in higher brain functions such as cognition, learning and memory formation (Birur et al., 2017, Fonnum, 1984, Headley and Grillner, 1990, Stanley et al., 2017), as well as in other plastic changes involved in the regulation of CNS development like synapse induction and elimination (Durand et al., 1996, Murphy-Royal et al., 2015, Rabacchi et al., 1992), and cell migration and differentiation (Campana et al., 2017, Komuro and Rakic, 1993, Rossi and Slater, 1993, Song et al., 2017). Glu concentration in the synaptic space is in the low micromolar range (3–4 μM) and around 10 μM in the extracellular fluid and in the cerebrospinal fluid (Danbolt, 2001, Hamberger and Nystrom, 1984, Lehmann et al., 1983). To maintain low Glu concentrations in the synaptic cleft below the affinity of its receptors, this amino acid is rapidly removed from the extracellular space by a family of sodium-dependent high-affinity transport systems located mainly in the plasma membrane of perisynaptic astrocytes, and in to a lower extent in neurons (Kanai et al., 1993). Once Glu is taken up, it is either used for metabolic purposes (like protein synthesis or energetic metabolism) or for its recycling as a transmitter (through the Glu/glutamine cycle). It is worth to mention that this biochemical shuttle is critical for Glu turnover (Danbolt, 2001). When the synaptic Glu concentration reaches a concentration in the millimolar range, an over-stimulation of its neuronal receptors triggers an excitotoxicity cascade in postsynaptic neurons (Maragakis and Rothstein, 2004). This cell death cascade is involved in pathological conditions that underlie neurodegenerative diseases (Brassai et al., 2015, Domingues et al., 2010, Gegelashvili and Bjerrum, 2014, Lauriat and McInnes, 2007, McEntee and Crook, 1993, Ribeiro et al., 2017). In order to understand this type of disorders and by these means develop alternatives for their treatment, it is important to characterize the mechanisms that regulate the expression of Glu transporters.