Receptor Oligomerization as a Process Modulating Cellular Semiotics

Abstract

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite of the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels.

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

“…Identifying a set of amino acids, including conserved residues such as Trp and Arg, at the receptor–receptor interface that may assist the oligomerization process is crucial. Receptor oligomerization has been considered a fundamental molecular mechanism which controls redundancy among GPCRs in various cell types [ 96 ]. To clarify the functional and evolutionary mechanisms of oligomerization, primary and tertiary structures of proteins, aggregation propensities of receptors, and free energies of dissociation of complexes have been analyzed [ 97 ].…”

Are Olfactory Receptors Really Olfactive?

“…Recent evidence that makes the odor activation mechanism more complex than expected is the finding that some olfactory receptors are made functional if, and only if, co-expressed with adrenergic receptors along the plasma membrane of olfactory neurons (Hague et al 2004). The fact that oligomeric complexes are to be formed prior to receptor activation remind us of the importance of oligomerization, as a process mediating protein folding and receptor selection along the plasma membrane of many eukaryotic cells (Giorgi et al 2010). …”

“…This demonstrates that oligomerization may constitute a basic molecular mechanism allowing receptors to explore new combinatory affinities in relation to the chemical heterogeneity of the extracellular milieu (Szidonya et al 2008). However, this phenomenon could be interpreted as simply due to the chemical properties of the interacting molecular partners or, more profitably, as an example of how relationships, once conventionally established, may condition any further modulatory change of the related molecules (Giorgi et al 2010). In this latter case, the oligomeric assembly driven by natural selection may explore new possible interactions with environmental ligands and this would be experienced by the bearing organism as a meaningful adaptive response for its survival and persistence.…”