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Mol Neurobiol. 2019 Apr 10. doi: 10.1007/s12035-019-1580-8. [Epub ahead of print]

Acute Cocaine Enhances Dopamine D2R Recognition and Signaling and Counteracts D2R Internalization in Sigma1R-D2R Heteroreceptor Complexes.

Author information

1
Department of Neuroscience, Karolinska Institutet, Biomedicum (B0851). Solnavägen 9, 171 77, Stockholm, Sweden. dasiel.borroto.escuela@ki.se.
2
Department of Biomolecular Science, Section of Physiology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, 610 29, Urbino, Italy. dasiel.borroto.escuela@ki.se.
3
Observatorio Cubano de Neurociencias, Grupo Bohío-Estudio, Zayas 50, 62100, Yaguajay, Cuba. dasiel.borroto.escuela@ki.se.
4
Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
5
Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, 751 24, Uppsala, Sweden.
6
Department of Neuroscience, Karolinska Institutet, Biomedicum (B0851). Solnavägen 9, 171 77, Stockholm, Sweden.
7
Institute of Pharmacology, Department of Drug Addiction Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland.
8
Department of Life Sciences and Biotechnology (SVEB), University of Ferrara, Ferrara, Italy.
9
Department of Neuroscience, Karolinska Institutet, Biomedicum (B0851). Solnavägen 9, 171 77, Stockholm, Sweden. kjell.fuxe@ki.se.

Abstract

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 (δ1R) heteroreceptor complexes and the D2R protomer recognition, signaling and internalization in cellular models. We report the existence of D2R-δ1R 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 δ1R, cocaine (1 nM) significantly increased the D2R Bmax values over cells singly expressing D2R. CREB reporter luc-gene assay indicated that coexpressed δ1R 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-δ1R cells. These events were associated with a marked reduction of cocaine-induced internalization of D2R protomers in D2R-δ1R heteromer-containing cells vs D2R singly expressing cells as studied by means of confocal analysis of D2R-δ1R trafficking and internalization. Overall, the formation of D2R-δ1R heteromers enhanced the ability of cocaine to increase the D2R protomer function associated with a marked reduction of its internalization. The existence of D2R-δ1R heteromers opens up a new understanding of the acute actions of cocaine.

KEYWORDS:

Cocaine; Dimerization; Dopamine D2 receptor; Heteroreceptor complexes; Oligomerization; Sigma 1 receptor; Substance use disorder

PMID:
30972626
DOI:
10.1007/s12035-019-1580-8

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