2026-08-29T14:04:42Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/178462024-09-21T20:39:54Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927
Repisalud
author
Borroto-Escuela, Dasiel O
author
Narváez, Manuel
author
Romero-Fernández, Wilber
author
Pinton, Luca
author
Wydra, Karolina
author
Filip, Malgorzata
author
Beggiato, Sarah
author
Tanganelli, Sergio
author
Ferraro, Luca
author
Fuxe, Kjell
2024-02-10T20:01:14Z
2024-02-10T20:01:14Z
2019-04-10
10.1007/s12035-019-1580-8
1559-1182
Molecular neurobiology
http://hdl.handle.net/10668/13813
30972626
http://hdl.handle.net/20.500.12105/17846
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.
eng
Cocaine
Dimerization
Dopamine D2 receptor
Heteroreceptor complexes
Oligomerization
Sigma 1 receptor
Substance use disorder
Acute Cocaine Enhances Dopamine D2R Recognition and Signaling and Counteracts D2R Internalization in Sigma1R-D2R Heteroreceptor Complexes.
research article