Spatial and Temporal Aspects of Signaling by G-Protein–Coupled Receptors

Abstract

Signaling by G-protein-coupled receptors is often considered a uniform process, whereby a homogeneously activated proportion of randomly distributed receptors are activated under equilibrium conditions and produce homogeneous, steady-state intracellular signals. While this may be the case in some biologic systems, the example of rhodopsin with its strictly local singlequantum mode of function shows that homogeneity in space and time cannot be a general property of G-protein-coupled systems. Recent work has now revealed many other systems where such simplicity does not prevail. Instead, a plethora of mechanisms allows much more complex patterns of receptor activation and signaling: different mechanisms of proteinprotein interaction; temporal changes under nonequilibrium conditions; localized receptor activation; and localized second messenger generation and degradation-all of which shape receptor-generated signals and permit the creation of multiple signal types. Here, we review the evidence for such pleiotropic receptor signaling in space and time.

A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

“…This inhibitory action of Barbadin on ERK1/2 activation cannot be attributed to a non-specific off-target effect of the compound, on other components of the MAPK pathway since it did not affect ERK1/2 activation promoted by the EGF receptor. These results are therefore consistent with the notion that spatio-temporal GPCR-stimulated ERK1/2 activation occurs following clustering of receptor/β-arrestin in CCPs and endocytosis of the complex in endosomes949.…”

Related GPCRs couple differently to G s : preassociation between G protein and 5‐HT 7 serotonin receptor reveals movement of Gα s upon receptor activation

“…The resolution of crystal structures of several GPCRs in different states of activation has led to a tremendous development in the structural understanding of GPCRs and their mode of G protein activation (1, 2). In addition, the dynamics of receptor activation, followed by G protein and effector activation, have been extensively mapped (3); however, despite these recent developments, less progress has been made in understanding the mode of interaction between GPCRs and G proteins.…”

Activation processes in ligand‐activated G protein‐coupled receptors: A case study of the adenosine A2A receptor

“…However, this two-state perspective ignores the underlying complex conformational ensemble which better characterizes GPCRs under more native conditions. Recent spectroscopic studies including NMR [34][35][36][37][38][39][40][41][42][43], EPR [44], fluorescence [45][46][47][48], and BRET [49] have succeeded in elaborating on this complex conformational landscape while providing new insights into the dynamic facets of GPCRs. This creates new paradigms relating to mechanisms of activation of GPCRs and opportunities for medicinal intervention.…”