Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex

The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects

“…Scattered GABA interneurons located inter alia in the oriens and radiatum layers were also identified as being PLA positive. Taken together, the results indicate that the OXTR-5-HT2CR heterocomplexes represent a widespread integrative mechanism in the neuronal networks of the forebrain [31].…”

“…Using an intracellular calcium mobilization assay and a time-resolved fluorescencebased IP1 accumulation assay, it was possible to observe a significant attenuation of the OXTR protomer-mediated Galphaq signaling by 5-HT2CR protomer activation [31]. As was the case for the 5-HT2AR protomer, in the 5-HT2AR-OXTR heterocomplex, the Galphaq signaling of the 5-HT2CR protomer was also less affected by the activation of the OXTR protomer.…”

“…OXTRs play a significant and impressive role in modulating social and cognitiverelated behaviors, like bonding and attachment, reward and motivation, as well as fear, anxiety and stress-related responses [57,58]. These modulations of the neuronal networks involve the formation of heteroreceptor complexes with other GPCRs, like 5-HT2AR, 5-HT2CR [30,31] and D2R [59,60]. The dynamic formation of OXTR-5-HT2AR, OXTR-5-HT2CR and OXTR-D2R heteroreceptor complexes, especially in the limbic cortex and nucleus accumbens, makes possible a fundamental integrative process in the plasma membrane for the modulation of social and cognitive behaviors.…”

“…Based on flow cytometry FRET and confocal microscopy, OXTR-5-HT2CR heterocomplexes were first demonstrated in vitro in living cells, followed by observations of their existence in the brain using proximity ligation assays [31]. They appeared to have a widespread distribution which is compatible with the OXTR and 5-HTR2C co-expression observed in mouse whole cortex and hippocampus and in human cortex following in silico analysis of the single cell RNA sequencing data available via the transcriptomic explorer in the Allen Brain Atlas (https://celltypes.brain-map.org/rnaseq/mouse_ctx-hip_smart-seq).…”

“…Modulation by serotonin VT of, e.g., glutamate and GABA synapses in the hippocampus involves 5-HT homoreceptor complexes and many different subtypes of 5-HT heteroreceptor complexes located on neurons and/or astroglia, like serotonin 1A receptor (5-HT1A)-fibroblast growth factor receptor 1 (FGFR1) [16][17][18][19], serotonin 1a receptor (5-HT1A)-serotonin 2A receptor (5-HT2A) [20], serotonin 1A receptor (5-HT1A)-galanin receptor 1 (GalR1) [21][22][23][24], serotonin 1A receptor (5-HT1A)-galanin receptor 1 (GalR1)galanin receptor 2 (GalR2) [25], serotonin 1A receptor (5-HT1A)-G-protein coupled receptor 39 (GPR39) [26], serotonin 2C receptor (5-HT2C)-growth hormone secretagogue receptor 1A (GHS-R1a) [27][28][29], serotonin 2A receptor (5-HT2A)-oxytocin receptor (OXTR) [30] and serotonin 2C receptor (5-HT2C)-oxytocin receptor (OXTR) [31] heteroreceptor complexes. One emerging concept in depression is that disturbances in allosteric receptor-receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing depression and become novel targets for the treatment of depression and anxiety [19,32,33].…”