G protein-coupled receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit. Using a peptide-based approach, we here report evidence for the existence of functional pre-coupled complexes of heteromers of adenosine A receptor and dopamine D receptor homodimers coupled to their cognate Gs and Gi proteins and to subtype 5 AC. We also demonstrate that this macromolecular complex provides the necessary frame for the canonical Gs-Gi interactions at the AC level, sustaining the ability of a Gi-coupled GPCR to counteract AC activation mediated by a Gs-coupled GPCR.
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Article Synopsis
- Recent research suggests that G protein-coupled receptors (GPCRs) can form oligomers that are important for their function.
- The essay explores how these oligomers exhibit unique biochemical characteristics, particularly in the context of allosterism, and discusses methods to identify them in both artificial systems and natural tissues.
- Advances in various scientific techniques have enhanced our understanding of GPCR oligomers and their role in larger macromolecular complexes, influencing interactions with ligands and other signaling proteins.
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