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Visualization of differential GPCR crosstalk in DRD1-DRD2 heterodimer upon different dopamine levelsopen access

Authors
Kim, HyunbinNam, Min-HoJeong, SohyeonLee, HyowonOh, Soo-JinKim, JeongjinChoi, NakwonSeong, Jihye
Issue Date
6월-2022
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Keywords
GPCR heterodimer; Dopamine receptor sensor; DRD1; DRD2; cAMP; Tonic and phasic DA release
Citation
PROGRESS IN NEUROBIOLOGY, v.213
Indexed
SCIE
SCOPUS
Journal Title
PROGRESS IN NEUROBIOLOGY
Volume
213
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/145920
DOI
10.1016/j.pneurobio.2022.102266
ISSN
0301-0082
Abstract
Dopaminergic signaling is regulated by transient micromolar (phasic) and background nanomolar (tonic) dopamine releases in the brain. These dopamine signals can be differentially translated by dopamine receptor type 1 and type 2, DRD1 and DRD2, which are G protein-coupled receptors (GPCRs). In response to dopamine, DRD1 and DRD2 are known to mediate opposite functions on cAMP production via Gs and Gi protein signaling. Interestingly, they can form a heterodimer. However, receptor crosstalk between DRD1-DRD2 heterodimers has not been directly measured, but it was only inferred from measuring downstream signaling pathways. Here we develop fluorescent protein-based multicolor biosensors which can monitor individual activation states of DRD1 and DRD2, and apply them to directly monitor the functional crosstalk between DRD1-DRD2 heterodimers in live cells. Utilizing these powerful tools, we surprisingly discover differential crosstalk in the DRD1-DRD2 heterodimers upon different dopamine (DA) levels: DRD1 activation is selectively inhibited at micromolar DA levels, while DRD2 is inhibited only by nanomolar DA concentration, implying a novel function of the DRD1-DRD2 heterodimer upon different DA levels. Our results imply differential receptor crosstalk and novel functions of the DRD1-DRD2 heterodimer in response to physiological dopamine levels from nanomolar to micromolar dopamine concentrations.
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