Abstract
The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.
Highlights
The concept of allosteric receptor–receptor interactions in which G protein-coupled receptor (GPCR) homo-and heteroreceptor complexes, physically interact with each other and adaptor proteins, provides a new dimension to molecular integration in the central nervous system (CNS)
This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks operating mainly via volume transmission to reach heteroreceptor complexes located in extrasynaptic and synaptic regions of neuronal cells and in astroglia
Inspired by the significant work of Kitayama et al [50] we proposed that certain postjunctional 5-HT1R subtypes may activate the fibroblast growth factor receptor FGFR2-FGFR1 system by forming a heteroreceptor complex leading to development of allosteric receptor–receptor interactions (Figure 2)
Summary
The concept of allosteric receptor–receptor interactions in which G protein-coupled receptor (GPCR) homo-and heteroreceptor complexes, physically interact with each other and adaptor proteins, provides a new dimension to molecular integration in the central nervous system (CNS). The heteroreceptor complexes present a novel biological principle for signal integration Their allosteric receptor–receptor interactions are bidirectional and the complexes represent novel targets for treatment of CNS diseases [1]. GalR1-GalR2-5-HT1AR heterocomplexes in mental disease, with a particular focus on major depression [9]. Based on the significant work on astrocytic control of limbic glutamatergic activity [13] having effects on serotoninergic dorsal raphe function, the role of astrocytes and their heteroreceptor complexes [14,15] is discussed in relation to depression and other mental diseases. In view of the negative effects of stress on depression development [16] the possible link of stress to effects on 5-HTR heterocomplexes, especially to 5-HT1A auto-receptor complexes in dorsal raphe serotonin neurons, is briefly discussed
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