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 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.

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

“…In support of this view, the A2AR protomer is known to put a brake on D2R signaling in the A2AR-D2R complex (Borroto-Escuela et al, 2018d). IL1R2, CCR2, and CXCR4 may also form heteroreceptor complexes with NMDAR and D2R, which is of relevance for the mild neuroinflammation hypothesis of Schizophrenia (Borroto-Escuela et al, 2017c). Therefore, there is the possibility that A2R activation produces its immunosuppressant actions through receptor-receptor interactions in A2AR-Chemokine/cytokine complexes on the T cell membrane.…”

Hydrogen Sulfide Affects Radical Formation in the Hippocampus of LPS Treated Rats and the Effect of Antipsychotics on Hydrogen Sulfide Forming Enzymes in Human Cell Lines

“…Changes in cytokine production, such as IL-1 or TNF-a in the LPS model are reported ( 85 ). Although several mechanisms report that H 2 S can exert its physiological effects, such as sulfhydration or hemeprotein interactions [for review see ( 31 )], other mechanisms, such as the influence on receptor heterocomplexes that are important in the pathophysiology of schizophrenia cannot be excluded from consideration ( 86 , 87 ).…”

The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines

“…For example, there is an evidence that CCL-11 at low concentrations can act as a partial agonist at CCR2 and antagonize CCL2 activity, but high concentrations are sufficient to activate CCR2 in chemotaxis assays [ 261 , 274 ]. Some receptors have been proposed to form putative heteroreceptor complexes with an NMDA receptor (NMDAR-CCR2, NMDAR-CXCR4) that may also contribute to schizophrenia-like symptoms in mild neuroinflammation [ 275 ]. The function of CX3CR1 seems to be the most characterized since this receptor binds single chemokine—CX3CL1, which is the only chemokine with the expression higher in the CNS than in the periphery [ 276 , 277 ].…”

“…Some chemokines (underlined here) that are altered in schizophrenia can bind to multiple receptors and they all act through increasing calcium transients. Based on [ 10 , 11 , 261 , 264 , 267 , 268 , 269 , 275 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 ].…”