期刊
CELLULAR SIGNALLING
卷 40, 期 -, 页码 116-124出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2017.09.007
关键词
Receptor heteromers; Synaptosomes; Release; Quinpirole; BD1063; HEK293T cells
类别
资金
- Swedish Medical Research Council [04X-715]
- Swedish Medical Research Council (VR-link)
- Parkinson Fonden
- Hjarnfonden [FO2016-0302]
The effects of nanomolar cocaine concentrations, possibly not blocking the dopamine transporter activity, on striatal D-2-sigma(1) heteroreceptor complexes and their inhibitory signaling over Gi/o, have been tested in rat striatal synaptosomes and HEK293T cells. Furthermore, the possible role of sigma(1) receptors (sigma 1RS) in the cocaine-provoked amplification of D-2 receptor (D2R)-induced reduction of K+-evoked [H-3]-DA and glutamate release from rat striatal synaptosomes, has also been investigated. The dopamine D-2-likeR agonist quinpirole (10 nM-1 mu M), concentration-dependently reduced K+-evoked [H-3]-DA and glutamate release from rat striatal synaptosomes. The sigma R-1 antagonist BD1063 (100 nM), amplified the effects of quinpirole (10 and 100 nM) on K+-evoked [H-3]-DA, but not glutamate, release. Nanomolar cocaine concentrations significantly enhanced the quinpirole (100 nM)-induced decrease of K+ evoked [3H]-DA and glutamate release from rat striatal synaptosomes. In the presence of BD1063 (10 nM), cocaine failed to amplify the quinpirole (100 nM)-induced effects. In cotransfected sigma R-1 and D2LR. HEK293T cells, quinpirole had a reduced potency to inhibit the CREB signal versus D2LR singly transfected cells. In the presence of cocaine (100 nM), the potency of quinpirole to inhibit the CREB signal was restored. In D2LR singly transfected cells cocaine (100 nM and 10 mu M) exerted no modulatory effects on the inhibitory potency of quinpirole to bring down the CREB signal. These results led us to hypothesize the existence of functional D-2-sigma R-1 complexes on the rat striatal DA and glutamate nerve terminals and functional D2-sigma R-1-DA transporter complexes on the striatal DA terminals. Nanomolar cocaine concentrations appear to alter the allosteric receptor-receptor interactions in such complexes leading to enhancement of Gi/o mediated D2R signaling.
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