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D2-like dopamine and β-adrenergic receptors form a signaling complex that integrates Gs- and Gi-mediated regulation of adenylyl cyclase

, : D2-like dopamine and β-adrenergic receptors form a signaling complex that integrates Gs- and Gi-mediated regulation of adenylyl cyclase. Cellular Signalling 24(11): 2051-2060

?-Adrenergic receptors (?AR) and D2-like dopamine receptors (which include D2-, D3- and D4-dopamine receptors) activate Gs and Gi, the stimulatory and inhibitory heterotrimeric G proteins, respectively, which in turn regulate the activity of adenylyl cyclase (AC). ?2-Adrenergic receptors (?2AR) and D4-dopamine receptors (D4DR) co-immunoprecipitated when co-expressed in HEK 293 cells, suggesting the existence of a signaling complex containing both receptors. In order to determine if these receptors are closely associated with each other, and with other components involved in G protein-mediated signal transduction, ?2AR, D4DR, G protein subunits (G?i1 and the G?1?2 heterodimer) and AC were tagged so that bioluminescence resonance energy transfer (BRET) could be used to monitor their interactions. All of the tagged proteins retained biological function. For the first time, FlAsH-labeled proteins were used in BRET experiments as fluorescent acceptors for the energy transferred from Renilla luciferase-tagged donor proteins. Our experiments revealed that ?2AR, D4DR, G proteins and AC were closely associated in a functional signaling complex in cellulo. Furthermore, BRET experiments indicated that although activation of Gi caused a conformational change within the heterotrimeric protein, it did not cause the G?? heterodimer to dissociate from the G?i1 subunit. Evidence for the presence of a signaling complex in vivo was obtained by purifying ?AR from detergent extracts of mouse brain with alprenolol Sepharose and showing that the precipitate also contained both D2-like dopamine receptors and AC. The fluorescent reagent FlAsH can be used as an acceptor in BRET experiments. ?2-Adrenergic and D4-dopamine receptors, Gs, Gi and adenylyl cyclase form a complex. Gi activation does not cause the Gi? subunit to dissociate from the G?? heterodimer. Brain contains a complex of ?-adrenergic and dopamine receptors and adenylyl cyclase.


PMID: 22759790

DOI: 10.1016/j.cellsig.2012.06.011

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