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  • There are numerous theories of schizophrenia etiopathology a


    There are numerous theories of schizophrenia etiopathology and genetics is often taken into consideration [25]. The dopamine D2 receptor is important since it is blocked by typical antipsychotic drugs with high affinity which is correlated with the ability to control psychotic symptoms in schizophrenia. There are three polymorphisms in the D2 dopamine receptor gene found in the human population. Ala for Val substitution in position 96 (V96A) is localized in the second transmembrane domain in the region responsible for ligand binding. Pro310Ser (P310S) and Ser311Cys (S311C) substitutions are located in the third intracellular loop which is probably responsible for G protein coupling, and thus, due to their localization they may induce changes in protein functioning. There is evidence that these polymorphic changes are correlated with schizophrenia, with the strongest evidence for S311C [26], [27], [28], [29], although relatively little work has been done on the subject of polymorphism impact on molecular changes in dopamine receptor interactions [30].
    Materials and methods
    Discussion The etiology of schizophrenia is a very complex issue which so far has not had a straightforward elucidation. Over the last 20 years there have been many attempts to demonstrate the association of this psychiatric disorder with genetic factors, but the results of these studies are inconsistent. The fact that schizophrenia is often inherited [25] suggests that genetic factors may contribute to its development. Among others, polymorphic variants of the dopamine D2 receptors have been postulated as risk factors, however the functional role of these polymorphisms is far from clear. Dopamine receptors D1 and D2 are known to coexist on some of striatal neurons [8], [10]. Their capability to form heteromeric complexes has been confirmed several times [14], [15]. The latest findings show that concomitant stimulation of both receptors results in the activation of the Gq protein [9], [23]. The functional consequences of this unique signaling pathway regulated by D1-D2 heteromers are abstruse. However, one can presume its association with schizophrenia since disrupted calcium homeostasis may result in structural and/or cognitive brain deficits and neuroleptics have been shown to regulate calcium signaling [23]. Furthermore, activation of the D1-D2 heteromer with a selective ligand causes activation of calcium/calmodulin-dependent protein kinase IIα [17] and up regulated expression of the brain-derived neurotrophic factor [9] – two proteins whose connection with schizophrenia has been well documented [19], [20], [21], [25]. Three identified variants of the dopamine D2 receptor with amino sirtuin substitutions V96A, P310S and S211C have been shown to be connected with schizophrenia and/or an antipsychotic response. They might cause changes in the pharmacological profile or signal transduction, especially since the first polymorphic mutation is localized in N-terminal part of the second extracellular loop forming a ligand binding pocket and the two others are localized in the third intracellular loop responsible for G protein binding [39], [40]. Recent studies have identified the amino acids responsible for the D1-D2 heteromer formation [41]. The authors of this work emphasize the role of two arginine residues localized in the third intracellular loop of the dopamine D2 receptor. In the context of this discovery, it is likely that conformational changes induced by the polymorphic mutations may influence the interaction with the dopamine D1 receptor. [3H]methylspiperone binding properties of the human D2 natural and polymorphic variants published by Cravchik et al. [27] did not show any significant differences. We confirmed these data using another antagonist − [3H]raclopride, in cells expressing different variants of the dopamine D2 receptor as well as D2 and D1 receptors (data not shown). Specific agonists of both dopamine receptors impact their heterodimerization. The value of the energy transfer between the dopamine D1 and the natural D2 receptors is higher when the cells are concurrently stimulated with chloro-APB and quinpirole – two specific ligands of dopamine D1 and D2 receptors, respectively, or with one agonist SKF83959 which is postulated to activate the hetero-dimer. The latter showed a similar effect on heterodimerization when the cells expressing the D2P310S and S311C forms were examined instead of the natural D2 receptor. In case of the V96A variant, increase in E value was not significant. Surprisingly, an opposite effect was observed after stimulation with a mixture of two specific ligands. In the cells expressing the D1 and P310S or S311C forms of the D2 receptor, energy transfer decreased significantly. Such results point to a difference in the compound SKF83959 action mechanism at the heterodimer level in comparison to the action of two agonists. As the topology of oligomeric receptors is not known, it is hard to conclude whether the observed changes are a result of association modification, or conformational changes. The latter, when they occur within the C-terminal part of GPCRs, do not exceed 0.2nm [42], [43]. As the R0 value for mCherry and EGFP is known [44], [45], the measured FRET efficiencies may be used to calculate the distance between fluorescence proteins fused to the dopamine receptors in each configuration. The calculation results indicate that the observed changes in FRET efficiency depend on modifications of GPCRs association level in the plasma membrane in all the discussed cases apart from the D1-D2S311C heteromer stimulated by two specific ligands and the D1-D2V96A heteromer stimulated by SKF83959.