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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
Author(s) -
Goolam Mahvash A.,
Ward James H.,
Avlani Vimesh A.,
Leach Katie,
Christopoulos Arthur,
Conigrave Arthur D.
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.07.022
Subject(s) - phospholipase c , calcium sensing receptor , adenylyl cyclase , extracellular , phosphoinositide phospholipase c , microbiology and biotechnology , signal transduction , receptor , calcium signaling , mutant , gq alpha subunit , phosphorylation , intracellular , chemistry , biology , calcium , g protein , biochemistry , calcium metabolism , gene , organic chemistry
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 2+ (Ca 2+ 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 Ca 2+ o ‐stimulated ERK 1/2 phosphorylation. Ca 2+ o ‐stimulated intracellular Ca 2+ (Ca 2+ 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.