Roles of intraloops-2 and -3 and the proximal C-terminus in signalling pathway selection from the human calcium-sensing receptor

Mahvash Ayesha Goolam, James H Ward, Vimesh Ashvinkumar Avlani, Katherine Leach, Arthur Christopoulos, Arthur Conigrave

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

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 Ca2+ (Ca2+o)-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 Ca2+o-stimulated ERK1/2 phosphorylation. Ca2+o-stimulated intracellular Ca2+ (Ca2+i) 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.
Original languageEnglish
Pages (from-to)3340 - 3346
Number of pages7
JournalFEBS Letters
Volume588
Issue number18
DOIs
Publication statusPublished - 2014

Cite this

Goolam, Mahvash Ayesha ; Ward, James H ; Avlani, Vimesh Ashvinkumar ; Leach, Katherine ; Christopoulos, Arthur ; Conigrave, Arthur. / Roles of intraloops-2 and -3 and the proximal C-terminus in signalling pathway selection from the human calcium-sensing receptor. In: FEBS Letters. 2014 ; Vol. 588, No. 18. pp. 3340 - 3346.
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abstract = "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 Ca2+ (Ca2+o)-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 Ca2+o-stimulated ERK1/2 phosphorylation. Ca2+o-stimulated intracellular Ca2+ (Ca2+i) 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.",
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Roles of intraloops-2 and -3 and the proximal C-terminus in signalling pathway selection from the human calcium-sensing receptor. / Goolam, Mahvash Ayesha; Ward, James H; Avlani, Vimesh Ashvinkumar; Leach, Katherine; Christopoulos, Arthur; Conigrave, Arthur.

In: FEBS Letters, Vol. 588, No. 18, 2014, p. 3340 - 3346.

Research output: Contribution to journalArticleResearchpeer-review

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