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  • Structural changes within the heteromer induced by agonist a

    2020-11-20

    Structural changes within the heteromer induced by agonist administration show a high level of complication. The presented results obtained in quantitative FLIM-FRET measurements with two selective ligands match the qualitative conclusions indicated by changes in the intracellular calcium level. The polymorphic variants perturb synergistic actions of two specific ligands causing a decrease in the level of constitutive and induced association. Calcium ions release reflects the level of constitutive association, with the strongest effect observed in the case of the S311C variant of the D2 receptor. However, this is not the case when the Piericidin A are stimulated with SKF83959 which has been shown to activate the D1-D2 heteromer through concurrent interaction with the D1 and D2 receptors [23]. A functional role of polymorphic alterations in the dopamine D2 receptor has never been the object of extensive studies. In our laboratory we have confirmed that these polymorphic changes do not affect antagonist binding parameters. Cravchik et al. [27] have shown that point mutations within the third intracellular loop do not inhibit cAMP synthesis. A hypothesis that polymorphic changes affect the interactions with the Gαq proteins provide a possible explanation for the presented data which however has not been confirmed yet. Another interesting insight into the role of polymorphic changes within the dopamine D2 receptor is the observation that mutation in position 311 resulted in impaired sequestration of this receptor after dopamine stimulation [46]. This is also consistent with the present results indicating that the cells expressing the D1 and D2S311C receptors and activated with SKF83959 showed the highest increase in intracellular calcium level and FRET efficiency as compared with the initial value. Previously published results indicate that this genetic variant (when co-expressed with the D1 receptor) increases the D1 dopamine receptor affinity for clozapine [30] which in turn conforms with the fact that patients suffering from this illness require shorter hospitalization time [46]. Data presented in this paper confirm the hypothesis on the role of calcium signaling regulated by the D1-D2 heteromer with illness etiology. The results obtained for the S311C polymorphic variant of the dopamine D2 receptor strongly support this theory.
    Conflict of interest
    Acknowledgments This work was supported by grants from the Ministry of Science (N N302 113337). The Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University is a beneficiary of the European Union structural grant “Molecular Biotechnology for Health” – POIG 02.01.00-12-064/08. The equipment purchased in the frame of this grant has been used for the experiments described in this study.
    Introduction The capacity limit of working and short-term memory is the number of elements that are remembered for a short retention interval [1]. Memory capacity (MC) is impaired in many human pathologies such as ageing and schizophrenia [2,3]. Accumulating evidence consistently shows that schizophrenic patients have difficulties in performing working or short-term memory capacity/span tasks that tap into different memory domains [2,[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]]. Therefore, the pharmacology of MC is receiving much attention by studies in humans and in rodents [[20], [21], [22], [23], [24]]. Dopaminergic drugs have been shown to modulate working memory (WM) [[25], [26], [27], [28], [29], [30], [31], [32]]. Pioneer work on the role of dopamine (DA) on working memory has pointed to a specific function of D1 receptor activation for delay-dependent processing of information [26,[33], [34], [35]]. However, the specific role of DA receptors subtypes in modulating the capacity of WM is mostly unexplored in pre-clinical literature. To our knowledge, there is one pre-clinical study showing that D2- but not D1-receptor agonists improve MC in rodents [20]. Human studies support a role of D2-receptors in regulating MC, but D2 agonists and antagonists have been shown to improve and to impair MC in healthy subjects, depending on the dose, on the type of drug, on pre-existing individual differences in MC and on the type of tasks used to test MC [20,36,37]. In rodents, D2-like, but not D1-like, receptor agonists seem to improve MC [20]. To our knowledge, there is only one study in humans testing the effects of the D1 receptor antagonist, SCH 23390, on memory capacity; it showed that SCH 23390 has detrimental effects on spatial working memory capacity [38].