Measurements of the absolute levels of expression of GPCRs and G proteins invariably conclude that the G proteins are in considerable molar excess with regard to any specific GPCR [17-18]. This poses certain problems in pharmacology, because models of GPCR-G protein function that are both robust and predictive in nature derive from the premise that [GPCR] > [G protein]. Furthermore, the distribution of GPCRs and G proteins in the plasma membrane is non-random. Although the literature on the distribution of GPCRs is both large and complex, the equivalent literature for G proteins is relatively straightforward. Rather than being equally and randomly distributed, a substantial proportion of cellular G protein is targeted to, and located in, lipid 'rafts'. These are specialized structures enriched in cholesterol and sphingolipids that are both relatively resistant to dissolution by treatment with detergents and have low buoyant density . This has allowed enrichment of such fractions on sucrose and other density gradients as 'detergent-insensitive' or 'detergent-resistant' membrane domains that contain only a small fraction of total membrane protein. They tend to be heavily enriched in G proteins because anchorage of G protein a subunits to the plasma membrane is, at least in part, determined by the covalent attachment of a pair of fatty acids to sites near the G protein N terminus [20-21] and such modified proteins partition selectively into such rafts.
A clear understanding of the plasma membrane distribution of GPCRs is therefore required in order to appreciate effects of G proteins on GPCR constitutive activity, because raft-associated GPCRs would be expected to be in a G protein-enriched environment in relation to a raft-excluded GPCR. There are limited direct data on this issue. However, it is intriguing that the b2AR is generally accepted as displaying greater constitutive activity that the closely related P:AR (see Chapter 9 for further details). In cardiomyocytes it has been reported that the b2AR is more obviously raft-delineated than the P:AR [22-23]. Is the accompanying higher concentration of the stimulatory G protein Gs, then, an explanation for this? One effort to address this issue was to build GPCR-G protein fusion proteins between the long isoform of Gas and both the P:AR and the b2AR. These constructs define a 1:1 GPCR to G protein stoichiometry, and when these were expressed similar levels of constitutive activity were noted . Although indirect, such studies are consistent with the idea that higher levels of constitutive activity of the b2AR are indeed due to cellular compartmentation into rafts that are heavily enriched with G proteins.
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