Biased signaling agonist of dopamine D3 receptor induces receptor internalization independent of β-arrestin recruitment
| Autor: | Wei Xu, Lee-Yuan Liu-Chen, Sandhya Kortagere, Maarten E. A. Reith |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Dopamine media_common.quotation_subject education CHO Cells Butylamines 03 medical and health sciences Cricetulus 0302 clinical medicine Dopamine receptor D3 Cell surface receptor Cell Line Tumor Arrestin Functional selectivity medicine Animals Humans Receptor Internalization beta-Arrestins media_common G protein-coupled receptor Pharmacology Receptors Dopamine D2 Chemistry Receptors Dopamine D3 Cell biology Protein Transport HEK293 Cells 030104 developmental biology 030220 oncology & carcinogenesis Dopamine Agonists Signal Transduction |
| Zdroj: | Pharmacological Research. 143:48-57 |
| ISSN: | 1043-6618 |
| DOI: | 10.1016/j.phrs.2019.03.003 |
| Popis: | Agonist-induced internalization of G protein-coupled receptors (GPCRs) is a significant step in receptor kinetics and is known to be involved in receptor down-regulation. However, the dopamine D3 receptor (D3R) has been an exception wherein agonist induces D3Rs to undergo desensitization followed by pharmacological sequestration - which is defined as the sequestration of cell surface receptors into a more hydrophobic fraction within the plasma membrane without undergoing the process of receptor internalization. Pharmacological sequestration renders the receptor in an inactive state on the membrane. In our previous study we demonstrated that a novel class of D3R agonists exemplified by SK608 have biased signaling properties via the G-protein dependent pathway and do not induce D3R desensitization. In this study, using radioligand binding assay, immunoblot or immunocytochemistry methods, we observed that SK608 induced internalization of human D3R stably expressed in CHO, HEK and SH-SY5Y cells which are derived from neuroblastoma cells, suggesting that it is not a cell-type specific event. Further, we have evaluated the potential mechanism of D3R internalization induced by these biased signaling agonists. SK608-induced D3R internalization was time- and concentration-dependent. In comparison, dopamine induced D3R upregulation and pharmacological sequestration in the same assays. GRK2 and clathrin/dynamin I/II are the key molecular players in the SK608-induced D3R internalization process, while β-arrestin 1/2 and GRK-interacting protein 1(GIT1) are not involved. These results suggest that SK608-promoted D3R internalization is similar to the type II internalization observed among peptide binding GPCRs. |
| Databáze: | OpenAIRE |
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