title: IL1R2, CCR2, and CXCR4 May Form Heteroreceptor Complexes with NMDAR and D2R: Relevance for Schizophrenia.
abstract: The mild neuroinflammation hypothesis of schizophrenia was introduced by Bechter in 2001. It has been hypothesized that a hypofunction of glutamatergic signalingvia 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.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Biomolecular Science, Section of Physiology, Campus Scientifico Enrico Mattei, University of Urbino, Urbino, Italy; Observatorio Cubano de Neurociencias, Grupo Bohío-Estudio, Yaguajay, Cuba.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.affiliation: Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation , Saint Petersburg , Russia.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Tarakanov
authors.affiliation: Clinic for Psychiatry and Psychotherapy II, Ulm University, Bezirkskrankenhaus Günzburg , Günzburg , Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Bechter
authors.affiliation: Department of Neuroscience, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
keywords: NMDAR; chemokine receptors; cytokine receptors; heteroreceptor complexes; neuroinflamation; receptor–receptor interactions; schizophrenia; volume transmission