Two Signals from the Same Receptor

To help shed light on the question of why some receptors have more than one endogenous ligand, Kohout et al. characterized signaling by the CC chemokine receptor 7 (CCR7). CCR7 functions in directing a number of cellular events that direct migration of lymphocytes into the lymph nodes. There are two endogenous ligands for CCR7. One, CCL21, is found on the high endothelial venules (specialized vessels through which lymphocytes leave the blood and enter the lymph nodes); the other, CCL19, is found in the T cell zone of lymph nodes (where T cells congregate separated from B cells). CCR7 is a G protein-coupled receptor, and such receptors normally undergo desensitization; that is, after initial exposure to ligand, they become uncoupled from further activation of G proteins. Kohout et al. treated cells from the human T cell lymphoma cell line H9 with CCL19 and found that CCR7 molecules in isolated membranes were desensitized to further stimulation by CCL19 or CCL21. However, even though CCL21 was equally potent to CCL19 in activating G protein signaling through CCR7, CCL21 did not cause receptor desensitization. In studies of human embryonic kidney 293 cells overexpressing tagged versions of CCR7 and β-arrestin2, the authors showed that CCL21 also failed to cause recruitment of β-arrestin2 to the receptor complex and had a weaker effect on activation of the mitogen-activated protein kinases ERK1 and ERK2 than did CCL19. Thus, CCR7 appears to adopt different conformations when bound to CCL19 and CCL21. Both receptor states can activate G protein signaling, but recruitment of β-arrestin and consequent desensitization and signaling through ERKs are produced primarily by the CCL19-containing complex. This should allow distinct cellular responses to be mediated through the same receptor by the two ligands and could be a useful property of such receptors to exploit in the development of highly selective therapeutic agents. T. A. Kohout, S. L. Nicholas, S. J. Perry, G. Reinhart, S. Junger, R. S. Struthers, Differential desensitization, receptor phosphorylation, β-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J. Biol. Chem . 279 , 23214-23222 (2004). [Abstract] [Full Text]