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

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-HT_2A 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: A_2A–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 A_2A–D₂–mGluR5 and CB₁–D₂–A_2A 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-HT_2A 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 A_2A, 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.