Tails of the unexpected - an atypical receptor for the chemokine RANTES/CCL5 expressed in brain.
Chemokines and their receptors play a central role in the trafficking of leukocytes within the body, a process which is amenable to antagonism by small molecules and which holds promise as a treatment for clinically important diseases. In the issue of the British Journal of Pharmacology accompanying this commentary, Ignatov and colleagues describe an unexpected role for the chemokine RANTES/CCL5, namely an ability to signal via the orphan G protein-coupled receptor named GPR75. This receptor bears little homology to other chemokine receptors, most strikingly within the putative intracellular domains, with the third loop and C-terminal tail dwarfing those of other known chemokine receptors. This most likely accounts for the atypical pertussis toxin-insensitive signalling induced by RANTES. Intriguingly, this signalling is neuro-protective, inducing the survival of a hippocampal cell line following insult with the neurotoxic amyloid-beta peptide. Since this peptide is implicated in the pathogenesis of Alzheimer's disease, it may be that exploitation of this signalling pathway presents itself as a future therapeutic treatment.
Pease
J E
JE
Leukocyte Biology Section, Faculty of Medicine, Imperial College London, National Heart and Lung Institute, South Kensington Campus, London, UK. j.pease@imperial.ac.uk
D001923:Brain Chemistry; D018946:Chemokine CCL5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019742:Chemokines, CC / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D019707:Receptors, Chemokine; D015398:Signal Transduction
C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D019707:Receptors, Chemokine