Visualization of differential GPCR crosstalk in DRD1-DRD2 heterodimer upon different dopamine levels. (June 2022)

• Record Type: Journal Article
• Authors: Kim, Hyunbin; Nam, Min-Ho; Jeong, Sohyeon; Lee, Hyowon; Oh, Soo-Jin; Kim, Jeongjin; Choi, Nakwon; Seong, Jihye
• Is Part Of: Progress in neurobiology. Volume 213(2022)
• Publication Date: 2022-06
• Subjects: GPCR heterodimer -- Dopamine receptor sensor -- DRD1 -- DRD2 -- cAMP -- Tonic and phasic DA release; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2022.102266
• Languages: English
• ISSNs: 0301-0082

Abstract

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. Graphical Abstract: ga1 Highlights: ● Development of new red fluorescent DRD1 sensor (R-DRD1) and green DRD2 sensor (G-DRD2). ● Simultaneous monitoring of DRD1 and DRD2 activities by multicolor live-cell imaging. ● Differential crosstalk in the DRD1-DRD2 heterodimer upon different dopamine levels.