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Acute Cocaine Enhances Dopamine D2R Recognition and Signaling and Counteracts D2R Internalization in Sigma1R-D2R Heteroreceptor Complexes
Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden; Univ Urbino, Dept Biomol Sci, Sect Physiol, Campus Sci Enrico Mattei, Urbino, Italy; Grp Bohio Estudio, Observ Cubano Neurociencias, Yaguajay, Cuba.ORCID iD: 0000-0002-5736-373X
Univ Malaga, Inst Invest Biomed Malaga, Fac Med, Malaga, Spain.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
Karolinska Inst, Dept Neurosci, Biomed, Stockholm, Sweden.
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2019 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 56, no 10, p. 7045-7055Article in journal (Refereed) Published
Abstract [en]

The current study was performed to establish the actions of nanomolar concentrations of cocaine, not blocking the dopamine transporter, on dopamine D2 receptor (D2R)-sigma 1 receptor (delta 1R) heteroreceptor complexes and the D2R protomer recognition, signaling and internalization in cellular models. We report the existence of D2R-delta 1R heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum, with different distribution patterns using the in situ proximity ligation assay. Also, through BRET, these heteromers were demonstrated in HEK293 cells. Furthermore, saturation binding assay demonstrated that in membrane preparations of HEK293 cells coexpressing D2R and delta 1R, cocaine (1 nM) significantly increased the D2R B-max values over cells singly expressing D2R. CREB reporter luc-gene assay indicated that coexpressed delta 1R significantly reduced the potency of the D2R-like agonist quinpirole to inhibit via D2R activation the forskolin induced increase of the CREB signal. In contrast, the addition of 100 nM cocaine was found to markedly increase the quinpirole potency to inhibit the forskolin-induced increase of the CREB signal in the D2R-delta 1R cells. These events were associated with a marked reduction of cocaine-induced internalization of D2R protomers in D2R-delta 1R heteromer-containing cells vs D2R singly expressing cells as studied by means of confocal analysis of D2R-delta 1R trafficking and internalization. Overall, the formation of D2R-delta 1R heteromers enhanced the ability of cocaine to increase the D2R protomer function associated with a marked reduction of its internalization. The existence of D2R-delta 1R heteromers opens up a new understanding of the acute actions of cocaine.

Place, publisher, year, edition, pages
2019. Vol. 56, no 10, p. 7045-7055
Keywords [en]
Cocaine, Sigma 1 receptor, Dopamine D2 receptor, Heteroreceptor complexes, Oligomerization, Dimerization, Substance use disorder
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-395427DOI: 10.1007/s12035-019-1580-8ISI: 000486010800027PubMedID: 30972626OAI: oai:DiVA.org:uu-395427DiVA, id: diva2:1365088
Funder
Swedish Research Council, 62X-00715-50-3The Swedish Brain FoundationAvailable from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23Bibliographically approved

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