Abstract
The status and use of transmembrane, extracellular and intracellular domains in oligomerization of heptahelical G-protein coupled receptors (GPCRs) are reviewed and for transmembrane assemblies also supplemented by new experimental evidence. The transmembrane-linked GPCR oligomers typically have as the minimal unit an asymmetric ~180 kDa pentamer consisting of receptor homodimer or heterodimer and a G-protein αβγ subunit heterotrimer. With neuropeptide Y (NPY) receptors, this assembly is converted to ~90 kDa receptor monomer-Gα complex by receptor and Gα agonists, and dimers/heteropentamers are depleted by neutralization of Gαi subunits by pertussis toxin. Employing gradient centrifugation, quantification and other characterization of GPCR dimers at the level of physically isolated and identified heteropentamers is feasible with labeled agonists that do not dissociate upon solubilization. This is demonstrated with three neuropeptide Y (NPY) receptors and could apply to many receptors that use large peptidic agonists.
Highlights
Protein oligomerization, a very frequent association of identical or non-identical protein chains, could be viewed as a general paradigm of protein organization
If not most, G-protein coupled receptors (GPCRs) responding to monoamines are usually detected as monomers associated with Gα subunit, which is the minimal functional unit of GPCR
Barring a few notable exemptions, GPCRs are characterized by low densities of expression [37]
Summary
A very frequent association of identical or non-identical protein chains, could be viewed as a general paradigm of protein organization. There is an overwhelming experimental evidence for Gαβγ complexes of the peptidic-agonist (and especially the neuropeptide) GPCR dimers as the physiological non-activated state of the receptors, and this applies to the prototypic rhodopsin (gray opsin) non-peptidic GPCR [21,22,23]. If not most, GPCRs responding to monoamines (and especially to catecholamines) are usually detected as monomers associated with Gα subunit, which is the minimal functional unit of GPCR activity [25] This may relate to the low stability of agonist binding, to high basal levels of circulating aminergic agonists, and to abundance of G-proteins Affinity of specific agonist peptides for the dimers could be much larger than for the monomers, as indicated by differences in cation sensitivity and cholate extraction The agonist-activated protomers or monomers could transduce through a monomeric or heteromeric GTPase, or via a non-GTPase molecule or complex, such as the heterodimeric βγ complex [36]
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