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

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 D(2) 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 D(2) 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 D(2) receptor activity in the nucleus accumbens, since it produces a reduction in the prefrontal glutamate drive from the mediodorsal nucleus. The following D(2) receptor containing heterodimers/receptor mosaics are of special interest to schizophrenia: A(2A)-D(2), mGluR5-D(2), CB(1)-D(2), NTS(1)-D(2) and D(2)-D(3) 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)-D(2)-mGluR5 and CB(1)-D(2)-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, CB(1) or NTS(1) agonists or combined therapies with some of these agonists combined with D(2)-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.

Fig. 1

Illustration of the possible existence of CB₁–D₂–A_2A and A_2A–D₂–mGluR5 receptor mosaics in different local circuits of the accumbal-pallidal GABA neurons projecting into the ventral pallidum reached by volume transmission signals. The extrasynaptic CB₁–D₂–A_2A receptor mosaic is inter alia located on the dendritic spines of these neurons and on the incoming synaptic glutamate terminals to these spines. Activation of the CB₁ receptors with CB₁ agonists in this receptor mosaic leads to inhibition D₂ recognition and signaling and removal of D₂–G_i-mediated inhibition of A_2A activated adenylate cyclase with a release of its brake on A_2A signaling as shown in the upper left (1). The postulated extrasynaptic A_2A–D₂–mGluR5 receptor mosaic is illustrated in another local circuit of the same neurons and mainly in the dendritic spines, but may also be located in the same local circuit as you find the CB₁–D₂–A_2A receptor mosaic. Combined activation of the A_2A and mGluR5 receptors in this receptor mosaic leads to synergistic inhibition of D₂ recognition and signaling as illustrated in the upper right (2)

Fig. 2

Illustration of the possible preferential location of the mGluR2–5-HT_2A heterodimer/receptor mosaic on the shafts of the apical dendrites of pyramidal nerve cells of the cerebral cortex. This receptor assembly may mainly have an extrasynaptic location and is reached by both glutamate and 5-HT through volume transmission within the extracellular space originating from the synaptic glutamate nerve terminals and from the varicosities of the 5-HT nerve terminal plexus. No 5-HT_2A receptors exist on the dendritic spines of the pyramidal nerve cells (see Jansson et al. 2001). In the upper part, the hallucinogenic signaling of d-LSD is indicated as it targets the mGluR2–5-HT_2A heterodimer/receptor mosaic. d-LSD can activate not only the G_q/11 but also the G_i/o-mediated hallucinogenic signaling of the 5-HT_2A receptors (Gonzalez-Maeso et al. 2008). Via the inhibitory 5-HT_2A–mGluR2 receptor interaction in the receptor assembly, the signaling of the mGluR2 is also reduced by d-LSD (Gonzalez-Maeso et al. 2008). The type of G protein involved in the mGluR2 signaling in this assembly is not known. Through glutamate activation of the mGluR2 receptor within this receptor assembly, the d-LSD-mediated hallucinogenic signaling over the G_i/o in the 5-HT_2A receptor becomes blocked through an inhibitory mGluR2–5-HT_2A receptor–receptor interaction at the G protein coupling level. The receptor interaction is complex, since at the same time the affinity of the 5-HT_2A receptor becomes increased upon the activation of the mGluR2 (Gonzalez-Maeso et al. 2008) suggesting a major conformational change in the 5-HT_2A receptor that results in altered G protein selection and an enhancement of 5-HT_2A recognition