Activation of G Protein–Coupled Receptors: Beyond Two-State Models and Tertiary Conformational Changes

Abstract

Transformation of G protein-coupled receptors (GPCRs) from a quiescent to an active state initiates signal transduction. All GPCRs share a common architecture comprising seven transmembrane-spanning alpha-helices, which accommodates signal propagation from a diverse repertoire of external stimuli across biological membranes to a heterotrimeric G protein. Signal propagation through the transmembrane helices likely involves mechanistic features common to all GPCRs. The structure of the light receptor rhodopsin may serve as a prototype for the transmembrane architecture of GPCRs. Early biochemical, biophysical, and pharmacological studies led to the conceptualization of receptor activation based on the context of two-state equilibrium models and conformational changes in protein structure. More recent studies indicate a need to move beyond these classical paradigms and to consider additional aspects of the molecular character of GPCRs, such as the oligomerization and dynamics of the receptor.

G Protein Activation by Serotonin Type 4 Receptor Dimers

“…However, a growing number of studies revealed dimerization/oligomerization of GPCRs (4 -8) mostly in heterologous cells (homo-or heterodimers) but also in native tissues or in vivo (dimers) (9 -13). In line with these observations, a recent report described crystal structures of the chemokine receptor CXCR4 that are consistent with the formation of homodimers (14).A relatively accepted model proposes that only one protomer in a dimer is fully activated, even when both binding sites are occupied (15)(16)(17)(18)(19). The activated protomer interacts with the G␣ subunit to accelerate GDP/GTP exchange.…”

“…A relatively accepted model proposes that only one protomer in a dimer is fully activated, even when both binding sites are occupied (15)(16)(17)(18)(19). The activated protomer interacts with the G␣ subunit to accelerate GDP/GTP exchange.…”

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

“…Theoretical modeling (Crozier et al, 2003;Spijker et al, 2006) and experimental data [Gether, 2000 (i.e., site-directed spin labeling, site-directed fluorescence quenching, sulfhydryl accessibility, disulfide cross-linking); see methods reviewed in Meng and Bourne, 2001;Hubbell et al, 2003;Kobilka, 2002;Park et al, 2008] show that receptor proteins exist as collections (termed "ensembles") of tertiary conformations. The differences in these conformations need not be large.…”

Optogenetic control of chemokine receptor signal and T-cell migration

“…S1) (12,13). This finding suggests that the transmembrane domains of PA-CXCR4, which originated from rhodopsin, compensate for the structural and mechanical stresses resulting from the chimeric design and that the bulky side chains around retinal are not significantly affected by the CXCR4 cytoplasmic domains.…”