The triplet puzzle theory indicates extensive formation of heteromers between opioid and chemokine receptor subtypes

2019

Front. Mol. Neurosci.

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G protein-coupled receptors (GPCRs) not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place, modulating the functions of the participating GPCR protomers. GPCRs can also form heteroreceptor complexes with ionotropic receptors and receptor tyrosine kinases modulating their function. Furthermore, adaptor proteins interact with receptor protomers and modulate their interactions. The state of the art is that the allosteric receptor-receptor interactions are reciprocal, highly dynamic and substantially alter the signaling, trafficking, recognition and pharmacology of the participating protomers. The pattern of changes appears to be unique for each heteromer and can favor antagonistic or facilitatory interactions or switch the G protein coupling from e.g., Gi/o to Gq or to beta-arrestin signaling. It lends a new dimension to molecular integration in the nervous system. Future direction should be aimed at determining the receptor interface involving building models of selected heterodimers. This will make design of interface-interfering peptides that specifically disrupt the heterodimer possible. This will help to determine the functional role of the allosteric receptor-receptor interactions as well as the integration of signals at the plasma membrane by the heteroreceptor complexes, vs. integration of the intracellular signaling pathways. Integration of signals also at the plasma membrane seems crucial in view of the hypothesis that learning and memory at a molecular level takes place by reorganization of homo and heteroreceptor complexes in the postsynaptic membrane. Homo and heteroreceptor complexes are in balance with each other, and their disbalance is linked to disease. Targeting heteroreceptor complexes represents a novel strategy for the treatment of brain disorders.

Section: The Class a Gpcr Heteromersmentioning

confidence: 99%

Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS

2019

Front. Mol. Neurosci.

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“…In the current article, using in situ proximity ligation assay (PLA), we report evidence for the existence of brain 5-HT1A–5-HT2A isoreceptor complexes validated in cellular models with bioluminescence resonance energy transfer (BRET). We also study their interface using the triplet puzzle theory , and how it compares with the interface in other 5-HT isoreceptor and heteroreceptor complexes. ,,, Antagonistic allosteric receptor–receptor interactions in these isoreceptor complexes were established in the frontal lobe, by which 5-HT2A agonist-induced activation of the 5-HT2A protomer strongly reduced the affinity of the 5-HT1A agonist binding sites of the 5-HT1A protomer. The current results open up a new molecular mechanism for how the function of inhibitory 5-HT1A and excitatory 5-HT2A isoreceptors ,, can become integrated in the brain.…”

Section: Introductionmentioning

confidence: 99%

Existence of Brain 5-HT1A–5-HT2A Isoreceptor Complexes with Antagonistic Allosteric Receptor–Receptor Interactions Regulating 5-HT1A Receptor Recognition

Tarakanov

et al. 2017

ACS Omega

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Studies on serotonin-selective reuptake inhibitors have established that disturbances in the ascending 5-HT neuron systems and their 5-HT receptor subtypes and collateral networks to the forebrain contribute to the etiology of major depression and are targets for treatment. The therapeutic action of serotonin-selective reuptake inhibitors is of proven effectiveness, but the mechanisms underlying their effect are still unclear. There are many 5-HT subtypes involved; some need to be blocked (e.g., 5-HT2A, 5-HT3, and 5-HT7), whereas others need to be activated (e.g., postjunctional 5-HT1A and 5-HT4). These state-of-the-art developments are in line with the hypothesis that the development of major depression can involve an imbalance of the activity between different types of 5-HT isoreceptors. In the current study, using in situ proximity ligation assay (PLA), we report evidence for the existence of brain 5-HT1A–5-HT2A isoreceptor complexes validated in cellular models with bioluminescence resonance energy transfer (BRET2) assay. A high density of PLA-positive clusters visualizing 5-HT1A–5-HT2A isoreceptor complexes was demonstrated in the pyramidal cell layer of the CA1–CA3 regions of the dorsal hippocampus. A marked reduction in the density of PLA-positive clusters was observed in the CA1 and CA2 regions 24 h after a forced swim test session, indicating the dynamics of this 5-HT isoreceptor complex. Using a bioinformatic approach, previous work indicates that receptors forming heterodimers demonstrate triplet amino acid homologies. The receptor interface of the 5-HT1A–5-HT2A isoreceptor dimer was shown to contain the LLG and QNA protriplets in the transmembrane and intracellular domain, respectively. The 5-HT2A agonist TCB2 markedly reduced the affinity of the 5-HT1A agonist ipsapirone for the 5-HT1A agonist binding sites in the frontal lobe using the 5-HT1A radioligand binding assay. This action was blocked by the 5-HT2A antagonist ketanserin. It is proposed that the demonstrated 5-HT1A–5-HT2A isoreceptor complexes may play a role in depression through integration of 5-HT recognition, signaling and trafficking in the plasma membrane in two major 5-HT receptor subtypes known to be involved in depression. Antagonistic allosteric receptor–receptor interactions appear to be involved in this integrative process.

“…It is of interest that a number of 5HT1A isoreceptor complexes and α2- and β-adrenergic isoreceptor complexes ( 78 ) also possess sets of LYS, LPF, and SLA protriplets that may assist in the formation of these isoreceptor complexes (Table 1 ). Previous work demonstrated also crosstalk between opioid and chemokine receptor subtypes ( 79 ) and extensive formation of heteromers take place between opioid and receptor subtypes according to the triplet puzzle theory ( 80 ). In Table 1 , we report some results from this study showing that LYS and LPF protriplets may also participate in opioid and chemokine isoreceptor complexes as well as in the delta opioid-CXCR4 heterodimer.…”

Section: Possible Molecular Mechanisms Based On the Triplet Puzzle Thmentioning

confidence: 99%

“…In Table 1 , we report some results from this study showing that LYS and LPF protriplets may also participate in opioid and chemokine isoreceptor complexes as well as in the delta opioid-CXCR4 heterodimer. Their possible role in schizophrenic symptoms in neuroinflammation remains to be explored, but they may have an impact on pain and reward mechanisms ( 80 ).…”

Section: Possible Molecular Mechanisms Based On the Triplet Puzzle Thmentioning

confidence: 99%

IL1R2, CCR2, and CXCR4 May Form Heteroreceptor Complexes with NMDAR and D2R: Relevance for Schizophrenia

Tarakanov

Bechter³

et al. 2017

Front. Psychiatry

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The mild neuroinflammation hypothesis of schizophrenia was introduced by Bechter in 2001. It has been hypothesized that a hypofunction of glutamatergic signaling via N-methyl-D-aspartate receptors (NMDARs) and hyperactivation of dopamine D2 receptors play a role in schizophrenia. The triplet puzzle theory states that sets of triplet amino acid homologies guide two different receptors toward each other and contributes to the formation of a receptor heteromer. It is, therefore, proposed that putative NMDAR-C-C chemokine receptor type 2 (CCR2), NMDAR-C-X-C chemokine receptor type 4 (CXCR4), and NMDAR- interleukin 1 receptor type II (IL1R2) heteromers can be formed in the neuronal networks in mild neuroinflammation due to demonstration of Gly-Leu-Leu (GLL), Val-Ser-Thr (VST), and/or Ser-Val-Ser (SVS) amino acid homologies between these receptor protomers. This molecular process may underlie the ability to produce symptoms of schizophrenia in mild neuroinflammation. In this state, volume transmission (VT) is increased involving increased extracellular vesicle-mediated VT from microglia and astroglia. These vesicles may contain CCR2, CXCR4, and/or IL1R2 as well as their ligands and upon internalization by endocytic pathways into neurons can form heteroreceptor complexes with NMDAR in the plasma membrane with pathological allosteric receptor–receptor interactions involving increased internalization and reduced NMDAR signaling. The triplet puzzle theory also suggests the formation of putative D2R-CCR2, D2R-CXCR4, and D2R-IL1R2 heteromers in mild neuroinflammation in view of their demonstrated sets of Leu-Tyr-Ser (LYS), Leu-Pro-Phe (LPF), and/or Ser-Leu-Ala (SLA) triplet homologies. These D2R heteroreceptor complexes may also contribute to schizophrenia-like symptoms in mild neuroinflammation by enhancing D2R protomer function.