PMID:24056371

Citation	'Gilliland, CT, Salanga, CL, Kawamura, T, Trejo, J and Handel, TM (2013) The chemokine receptor CCR1 is constitutively active, which leads to G protein-independent, β-arrestin-mediated internalization. J. Biol. Chem. '
Abstract	Activation of G protein-coupled receptors by their associated ligands has been extensively studied, and increasing structural information about the molecular mechanisms underlying ligand-dependent receptor activation is beginning to emerge with the recent expansion in GPCR crystal structures. However, some GPCRs are also able to adopt active conformations in the absence of agonist binding that result in the initiation of signal transduction and receptor down-modulation. In this report we show that the CC-type chemokine receptor 1 (CCR1) exhibits significant constitutive activity leading to a variety of cellular responses. CCR1 expression is sufficient to induce inhibition of cAMP formation, increased F-actin content, and basal migration of human and murine leukocytes. The constitutive activity leads to basal phosphorylation of the receptor, recruitment of β-arrestin-2 and subsequent receptor internalization. CCR1 concurrently engages Gαi and β-arrestin-2 in a multi-protein complex, which may be accommodated by homo-oligomerization or receptor clustering. The data suggests the presence of two functional states for CCR1; whereas receptor coupled to Gαi functions as a canonical GPCR albeit with high constitutive activity, the CCR1:β-arrestin-2 complex is required for G protein independent constitutive receptor internalization. The pertussis toxin-insensitive uptake of chemokine by the receptor suggests that the CCR1:β-arrestin-2 complex may be related to a potential scavenging function of the receptor, which may be important for maintenance of chemokine gradients and receptor responsiveness in complex fields of chemokines during inflammation.
Links	PubMed Online version:10.1074/jbc.M113.503797
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:CCR1		GO:0030335: positive regulation of cell migration	ECO:0000315:		P		Figure 1	complete CACAO 8671
HUMAN:CCR1	involved_in	GO:0030335: positive regulation of cell migration	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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