4.4 Review

Glutamate heteroreceptor complexes in the brain

Journal

PHARMACOLOGICAL REPORTS
Volume 70, Issue 5, Pages 936-950

Publisher

POLISH ACAD SCIENCES INST PHARMACOLOGY
DOI: 10.1016/j.pharep.2018.04.002

Keywords

Allosteric receptor-receptor interactions; Oligomerization; Heteroreceptor complexes; Metabotropic glutamate receptor; Ionotropic glutamate receptor; Extrasynaptic; Basal ganglia

Funding

  1. Swedish Medical Research Council [04x-715]
  2. Hjarnfonden [FO2016-0302]
  3. AFA Forsakring [130328]

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The existence of mGluR, NMDAR, AMPAR and putative KAR heteroreceptor complexes in synaptic and extrasynaptic regions of brain glutamate synapses represents a major integrative mechanism. Our aim in the current article is to analyze if the formation of the different types glutamate hetereceptor complexes involves the contribution of triplet amino acid homologies (protriplets) in a postulated receptor interface based on the triplet puzzle theory. Seven main sets (lists) of receptor pairs in databases were used containing various sets (lists) of human receptor heteromers and nonheteromers obtained from the available scientific publications including the publically available GPCR-hetnet database. Brain mGluR1mGluR5 and mGluR2-mGluR4 isoreceptor complexes were demonstrated with a predominant extrasynaptic localization at a post-and prejunctional localization. The existence of putative mGluR4-mGluR7 heteroreceptor complexes in the basal ganglia is proposed. Metabotropic glutamate receptor subtypes also participated in the formation of a large number of heteroreceptor complexes like mGluR1-A1R, mGluR5-A2AR, mGluR5-D2R and D2R-A2AR-mGluR5, located in relation to glutamate synapses, especially in the basal ganglia. A putative mGluR1-GABAB1/2 heterocomplex may also exist. NMDAR heteroreceptor complexes were also demonstrated as a fundamental integrative mechanism in the glutamate synapse and its extrasynaptic membranes. It represented fundamental work on inter alia NMDAR-mGluR5, NMDAR-D1R and NMDAR-D2R heteroreceptor complexes involving both antagonistic and facilitatory allosteric receptor-receptor interactions. As to AMPA receptors, a heterocomplex was found for the interaction between IFNgR1 and the AMPAR mediated via the subunit GluA1 which may be of relevance for neuroinflammation. AMPAR-D2R heteroreceptor complexes were also demonstrated. Besides glutamate heteroreceptor complexes and their allosteric receptor-receptor interactions, a significant mechanism for the functional crosstalk can also be phosphorylation and/or reorganization of adapter proteins with dynamic binding to the two receptors modulating the allosteric receptor mechanism. (c) 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

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