The calcium-sensing receptor (CaSR) couples to signalling pathways via intracellular loops 2 and 3, and the C-terminus. However, the requirements for signalling are largely undefined. We investigated the impacts of selected point mutations in iL-2 (F706A) and iL-3 (L797A and E803A), and a truncation of the C-terminus (R866X) on extracellular Ca<sup>2+</sup> (Ca<sup>2+</sup><inf>o</inf>)-stimulated phosphatidylinositol-specific phospholipase-C (PI-PLC) and various other signalling responses. CaSR-mediated activation of PI-PLC was markedly attenuated in all four mutants and similar suppressions were observed for Ca<sup>2+</sup><inf>o</inf>-stimulated ERK<inf>1/2</inf> phosphorylation. Ca<sup>2+</sup><inf>o</inf>-stimulated intracellular Ca<sup>2+</sup> (Ca<sup>2+</sup><inf>i</inf>) mobilization, however, was relatively preserved for the iL-2 and iL-3 mutants and suppression of adenylyl cyclase was unaffected by either E803A or R866X. The CaSR selects for specific signalling pathways via the proximal C-terminus and key residues in iL-2, iL-3.
Goolam, M. A., Ward, J. H., Avlani, V. A., Leach, K., Christopoulos, A., & Conigrave, A. D. (2014). Roles of intraloops-2 and -3 and the proximal C-terminus in signalling pathway selection from the human calcium-sensing receptor. FEBS Letters, 588(18), 3340–3346. https://doi.org/10.1016/j.febslet.2014.07.022