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Integrated signaling in heterodimers and receptor mosaics of different types of GPCRs of the forebrain: relevance for schizophrenia

  • Biological Psychiatry - Review Article
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Abstract

Receptor–receptor interactions within receptor heterodimers and receptor mosaics formed by different types of GPCRs represent an important integrative mechanism for signaling in brain networks at the level of the plasma membrane. The malfunction of special heterodimers and receptor mosaics in the ventral striatum containing D2 receptors and 5-HT2A receptors in cortical networks may contribute to disturbances of key pathways involving ventral striato-pallidal GABA neurons and mediodorsal thalamic prefrontal glutamate neurons that may lead to the development of schizophrenia. The ventral striatum transmits emotional information to the cerebral cortex through a D2 regulated accumbal–ventral pallidal–mediodorsal–prefrontal circuit which is of special interest to schizophrenia in view of the reduced number of glutamate mediodorsal–prefrontal projections associated with this disease. This circuit is especially vulnerable to D2 receptor activity in the nucleus accumbens, since it produces a reduction in the prefrontal glutamate drive from the mediodorsal nucleus. The following D2 receptor containing heterodimers/receptor mosaics are of special interest to schizophrenia: A2A–D2, mGluR5–D2, CB1–D2, NTS1–D2 and D2–D3 and are discussed in this review. They may have a differential distribution pattern in the local circuits of the ventral striato-pallidal GABA pathway, predominantly located extrasynaptically. Specifically, trimeric receptor mosaics consisting of A2A–D2–mGluR5 and CB1–D2–A2A may also exist in these local circuits and are discussed. The integration of receptor signaling within assembled heterodimers/receptor mosaics is brought about by agonists and allosteric modulators. These cause the intramembrane receptor–receptor interactions, via allosteric mechanisms, to produce conformational changes that pass over the receptor interfaces. Exogenous and endogenous cooperativity is discussed as well as the role of the cortical mGluR2–5-HT2A heterodimer/receptor mosaic in schizophrenia (Gonzalez-Maeso et al. 2008). Receptor–receptor interactions within receptor heterodimer/receptor mosaics of different receptors in the ventral striatum and cerebral cortex give novel strategies for treatment of schizophrenia involving, e.g., monotherapy with either A2A, mGluR5, CB1 or NTS1 agonists or combined therapies with some of these agonists combined with D2-like antagonists that specifically target the ventral striatum. In addition, a combined targeting of receptor mosaics in the ventral striatum and in the cerebral cortex should also be considered.

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Acknowledgment

This work was supported by the Swedish Research Council.

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Authors and Affiliations

  1. Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177, Stockholm, Sweden

    Kjell Fuxe & Daniel Marcellino

  2. Intramural Research Program, NIH, Department of Health and Human Services, National Institute on Drug Abuse, Baltimore, MD, USA

    Amina S. Woods

  3. Department of Biomedical Sciences, University of Modena, Modena, Italy

    Leo Giuseppina & Luigi F. Agnati

  4. IRCCS Lido, Venice, Italy

    Leo Giuseppina & Luigi F. Agnati

  5. Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy

    Tiziana Antonelli, Luca Ferraro & Sergio Tanganelli

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  1. Kjell Fuxe
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  2. Daniel Marcellino
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  3. Amina S. Woods
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  4. Leo Giuseppina
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  6. Luca Ferraro
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  7. Sergio Tanganelli
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  8. Luigi F. Agnati
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Correspondence to Kjell Fuxe.

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This review is dedicated to the special issue “Brain plasticity: aging and neuropsychiatric disorders”.

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Fuxe, K., Marcellino, D., Woods, A.S. et al. Integrated signaling in heterodimers and receptor mosaics of different types of GPCRs of the forebrain: relevance for schizophrenia. J Neural Transm 116, 923–939 (2009). https://doi.org/10.1007/s00702-008-0174-9

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