The specificity and molecular basis of alpha1-adrenoceptor and CXCR chemokine receptor dimerization.
It is now well established that rhodopsin-like, family-A G protein-coupled receptors (GPCRs) can exist within homo- and heterodimeric/oligomeric complexes. However, limited information is currently available on the molecular basis of these interactions or their selectivity. Using the alpha1-adrenoceptor family as a model, this has been examined using assays including coimmunoprecipitation, saturation bioluminescence resonance energy transfer (BRET), time-resolved fluorescence resonance energy transfer (FRET), and bimolecular fluorescence complementation. We demonstrate key roles for transmembrane helices I and IV in homodimeric/oligomeric interactions of the alpha1b-adrenoceptor and suggest that other interactions indicate that this GPCR can exist as a higher-order oligomeric complex. Literature reports on heterodimerization between chemokine receptor family members and the effects or otherwise of agonist ligands are complex. It was recently indicated that although the CXCR2 receptor is able to homodimerize, this is not the case for the closely related CXCR1 receptor and that these two GPCRs do not heterodimerize. We have reinvestigated these issues using combinations of coimmunoprecipitation, saturation BRET, and a novel endoplasmic reticulum-trapping strategy. Unlike the previous report, we demonstrate that CXCR1 is able to both homodimerize and heterodimerize with the CXCR2 receptor and that the relative affinity of these interactions suggests that with coexpression of these two GPCRs a random mixture of homo- and heterodimers will be present.
Milligan
Graeme
G
Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland. g.milligan@bio.gla.ac.uk
Wilson
Shirley
S
López-Gimenez
Juan F
JF
D000818:Animals; D019281:Dimerization; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000737:chemistry* / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000737:chemistry / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D018340:Receptors, Adrenergic, alpha-1; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B