Emerging models describing how GPCRs function to transduce signals from the outside to the inside of the cell have greatly expanded in the last decade as new information highlights the limitations of established models. While the tripartite model including the GPCRs, G proteins, and effectors remains intact, it is apparent that GPCRs utilize a growing list of additional protein binding partners to carry out their cellular actions. Newly recognized binding partners serve to regulate GPCR oligomerization, pharmacology, and subcellular targeting, as well as determine the strength and duration of receptor-mediated signalling events. In other cases, these binding partners serve as previously unrecognized effectors or adaptors/scaffolds for other signalling proteins that propagate hormone-directed cellular signalling events independent of G proteins. The interacting and regulatory proteins included in this chapter appear to be the first examples of many yet to be discovered. A full understanding of how these proteins interact with one another to modulate GPCR signalling in the CNS remains a formidable and exciting challenge for future research.

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