Spatially restricted G protein-coupled receptor activity via divergent endocytic compartments [Cell Biology]

December 27th, 2013 by Jean-Alphonse, F., Bowersox, S., Chen, S., Beard, G., Puthenveedu, M. A., Hanyaloglu, A. C.

Post-endocytic sorting of G protein-coupled receptors (GPCRs) is driven by their interactions between highly diverse receptor sequence motifs with their interacting proteins, such as PDZ-domain proteins. However, whether these diverse interactions provide an underlying functional specificity, in addition to driving sorting, is unknown. Here we identify GPCRs that recycle via distinct PDZ-ligand/PDZ-protein pairs exploit their recycling machinery primarily for targeted endosomal localization and signaling specificity. The luteinizing hormone receptor (LHR) and beta2-adrenergic receptor (B2AR), two GPCRs sorted to the regulated recycling pathway, underwent divergent trafficking to distinct endosomal compartments. Unlike B2AR which traffics to early endosomes (EE), LHR internalizes to distinct pre-early endosomes (pre-EE) for its recycling. Pre-EE localization required interactions of LHR C-terminal tail with the PDZ protein GIPC, inhibiting its traffic to EEs. Rerouting LHR to EEs, or EE-localized GPCRs to pre-EEs, spatially reprograms MAPK signaling. Furthermore, LHR-mediated activation of MAPK signaling requires internalization and is maintained upon loss of the EE compartment. We propose that combinatorial specificity between GPCR sorting sequences and interacting proteins dictates an unprecedented spatiotemporal control in GPCR signal activity.