Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

Abstract

The dimerization or even oligomerization of G protein coupled receptors (GPCRs) causes ongoing, controversial debates about its functional role and the coupled biophysical, biochemical or biomedical implications. A continously growing number of studies hints to a relation between oligomerization and function of GPCRs and strengthens the assumption that receptor assembly plays a key role in the regulation of protein function. Additionally, progress in the structural analysis of GPCR-G protein and GPCR-ligand interactions allows to distinguish between actively functional and non-signaling complexes. Recent findings further suggest that the surrounding membrane, i.e., its lipid composition may modulate the preferred dimerization interface and as a result the abundance of distinct dimeric conformations. In this review, the association of GPCRs and the role of the membrane in oligomerization will be discussed. An overview of the different reported oligomeric interfaces is provided and their capability for signaling discussed. The currently available data is summarized with regard to the formation of GPCR oligomers, their structures and dependency on the membrane microenvironment as well as the coupling of oligomerization to receptor function.

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…A functional and structural relationship exists between GPCR and HMN. GPCR can interact with several membrane components (Gahbauer and Böckmann, 2016) and play an important role in the formation of HMN, where they can function as sophisticated signaling processing centers (Kenakin, 2007). In this respect, the first aspect deserving consideration is the lipid environment.…”

“…When the complex forms, for instance, the quaternary structure could display novel specific allosteric sites (Agnati et al, 2008). Furthermore, RM are in the center of two complementary networks of interactions: HMN involving (A) the lipid environment (Gahbauer and Böckmann, 2016), (B) RAMP (Foord and Marshall, 1999), (C) RTK , and (D) membrane channels (Liu et al, 2006a;Gamo et al, 2015) and VMN leading to (E) modulation of the binding sites (Fuxe et al, 1998), (F) modulation of G protein activation (Ferrada et al, 2009), (G) modulation of the signaling cascade, among others, and (H) switching from G protein to β-arrestin signaling (Rashid et al, 2007;Rozenfeld et al, 2012).…”

“…These data suggested that phospholipids could act as direct allosteric modulators of GPCR activity. Lipids, however, can also be covalently bound to GPCR (see Gahbauer and Böckmann, 2016). Due to a post-translational modification called palmitoylation, the saturated fatty acid palmitic acid (16 carbons) can be added to C-terminal cysteine residues via a thioester-type bond (Chini and Parenti, 2009).…”

“…Receptor complexes can arise in the plasma membrane (see Gahbauer and Böckmann, 2016). An evident mechanism how membrane properties may regulate GPCR assembly in membrane nanodomains is due to hydrophobic forces coupled to a hydrophobic mismatch.…”

Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale

“…A matter of debate for more than a decade, it is now more widely accepted that various types of GPCRs undergo dimerization or higher-order oligomerization prior to activation [5], and although monomers in family type A GPCRs are functional, heteromerization appears to be fundamental in receptor trafficking and pharmacology [55]. Current views strongly point to the membrane microenvironment as the key modulator of GPCR oligomerization [54] and more specifically to cholesterol as the dimerization-inducing membrane component [54,104]. The availability of the crystal structure of the β2 adrenergic receptor provided not only the first experimental observation of direct interactions between a GPCR and cholesterol [33,63,114] but also led to elaborating about the importance of the sterol, necessary for the crystallization of the protein, in establishing the dimeric form of this receptor in the crystal lattice [33].…”