Fuxe and Borroto-Escuela laboratory

Summary of recent work in the laboratory on the GPCR heteroreceptor complexes in the brain and their function in health and disease and their relevance for development of novel treatments of brain diseases.

The introduction of the concept of direct physical receptor-receptor interactions in the plasma membrane originated from biochemical receptor binding studies showing that neuropeptides can modulate the affinity and density of monoamine receptors in membrane preparations in the early 1980s. These results indicated the existence of neuropeptide-monoamine receptor-receptor interactions in the plasma membrane. The first meeting on receptor-receptor interactions was held in Stockholm in 1986 (the organizers were Kjell Fuxe and Luigi Agnati). The proceedings were published in 1987. In 1993 the allosteric receptor-receptor interactions were proposed to take place in heterodimers in balance with homodimers (Zoli et al.1993, Mol. Neurobiol. 7,294-394).

The concept of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) homo- and heteroreceptor complexes, in which they physically interact provides a new dimension to molecular integration in the brain. The receptor-receptor interactions dynamically change recognition, pharmacology, signaling and trafficking of the participating receptors and thus their function.
We introduced a novel hypothesis that vulnerability of distinct GPCR heteroreceptor complexes can be a major cause for brain disorders involving dramatic dysfunction through mark changes in their densities and allosteric receptor-receptor interactions.

    Illustration of fuxe research focus
    Illustration of the antagonistic allosteric receptor-receptor interactions in the A2AR-D2R heteroreceptor complexes with several possible receptor stoichiometries

    Recent work

    Fundamental concepts

    Concepts introduced by our group on GPCR heteroreceptor complexes and their integrative receptor-receptor interactions in the CNS for understanding brain integration and providing novel treatments of brain disease.

    Cocaine and morphine addiction

    Understanding integrative molecular mechanisms involving especially A2AR-D2R heteroreceptor complexes and their receptor-receptor interactions but also MOR-D2likeR heteroreceptor complexes.

    It will help elucidate cocaine and morphine addiction and open up novel treatment options of these types of addiction.

    Depression

    Understanding integrative molecular mechanisms involving especially FGFR1-5-HT1A heteroreceptor complexes and their receptor-receptor interactions but also 5-HT1A-5-HT2A and other 5-HT1A and also oxytocin heteroreceptor complexes.

    This research may help us understand depression and provide novel, antidepressant drugs, especially of treatment resistant depression.

    Schizophrenia

    Understanding integrative molecular mechanisms involving especially A2AR-D2R heteroreceptor complexes and their receptor-receptor interactions in ventral striatum in relation to schizophrenia.

    The role of distinc immune receptors and their potential physical interactions with NMDAR and D2R are also proposed to play a significant role in schizophrenia.

    This research has led to the A2AR hypothesis of schizophrenia with A2AR-D2R complexes having a significant role. Targeting these complexes may lead to development of novel antipsychotic drugs.

    Parkinson's disease

    Understanding integrative molecular mechanisms involving especially A2AR-D2R heteroreceptor complexes and their receptor-receptor interactions in dorsal striatum is of high relevance to see what goes wrong in sensory-motor integration in Parkinson’s disease.

    This research has led to the hypothesis that disturbances in A2AR-D2R, A2AR-mGluR5 and A2AR-D2R-mGluR5 complexes have a significant role in Parkinsonn’s disease by enhancing the brake in motor activation. It is produced through overactivity in the dorsal striato-pallidal GABA pathway induced by inhibition of the inhibitory D2R function in the receptor complexes present in this pathway.

    Targeting these complexes may lead to development of novel antiparkinsonian drugs.

    Group members