Tails of the unexpected - an atypical receptor for the chemokine RANTES/CCL5 expressed in brain

Abstract

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.

Figure 1

The RANTES/CCL5 signalling cascade mediated via the novel chemokine receptor, GPR75. Inhibition of observed signalling by the use of wortmannin and U73122 is also shown. Although the involvement of PKC in this pathway has not been directly demonstrated, activation of PKC has been previously reported to enhance the survival of the HT22 murine hippocampal cell line (Maher, 2001). Note the large third intracellular loop linking transmembrane helices V and VI and also the long C-terminus extending from transmembrane helix VII. These regions of GPR75 are anticipated to interact with the heterotrimeric G protein and may account for the atypical signalling described by Ignatov et al. (2006).