Functional Effects Of Gpcr Oligomerization

There are numerous examples of natural ligands disrupting GPCR oligomeric complexes, in some cases inducing or stabilizing them, and in other instances having no effect on their status of association [35-38]. The absence of apparent consistent functional effects has been one of the features that critics of this phenomenon have focused on in supporting the concept of artifactual association of many of these receptors [3]. Nevertheless, there are adequate examples of clear and substantial functional effects to support the potential importance of GPCR association. Proposed functional roles for GPCR dimerization or oligomerization have spanned modifications of protein folding and intracel-lular trafficking, the selectivity of ligand binding and activation, the selectivity of G protein association, the efficiency of signal transduction, and the physiological functions observed.

One of the most interesting functional effects is the possibility of changing biological responsiveness of a receptor system. There is the possibility that a dimeric or oligomeric GPCR complex could bind and be activated by a distinct ligand that would not bind or activate a monomeric receptor. The best current example of this is 6'-guanidinonaltrindole, a delta and kappa opioid heterodi-mer-selective agonist [39]. Targeting of a broad variety of heterodimeric complexes of GPCRs has become an attractive goal for pharmaceutical companies to increase the specificity of drugs that are in development. There is also the possibility that dimeric or oligomeric GPCR complexes would couple to different effectors and result in distinct signaling events in the cell. Here, too, this is more theoretical than definitively established, but it may serve as an explanation for differences in signaling observed in distinct cellular backgrounds.

Another potentially important group of functional effects is the ability of binding to one protomer of a dimeric or oligomeric complex to result in functional effects on other receptor protomers in the complex. This has been termed asymmetry of action, with the occupation of one protomer resulting in G protein coupling to the associated protomer or to the internalization of the associated protomer. This might also manifest itself as positive or negative cooperativity, where the binding of a ligand molecule to a receptor changes the properties of binding the next ligand molecule to that receptor or to the other receptor protomer within a complex. Indeed, this phenomenon has been demonstrated for many members of this superfamily [40, 41] . The molecular basis of the cooperativity events will need to be sorted out, as it may be distinct for receptors in different families or for unique pairs of receptors in a given family.

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