Roles of intraloops‐2 and ‐3 and the proximal C‐terminus in signalling pathway selection from the human calcium‐sensing receptor. Issue 18 (28th July 2014)

• Record Type: Journal Article
• Authors: Goolam, Mahvash A.; Ward, James H.; Avlani, Vimesh A.; Leach, Katie; Christopoulos, Arthur; Conigrave, Arthur D.
• Is Part Of: FEBS letters. Volume 588:Issue 18(2014)
• Page Start: 3340
• Page End: 3346
• Publication Date: 2014-07-28
• Subjects: GPCR -- G-protein coupled receptor -- CaSR -- calcium-sensing receptor -- PI-PLC -- phosphatidylinositol-specific phospholipase-C -- VFT -- Venus FlyTrap -- CR -- Cysteine-rich -- iL -- intraloop -- cAMP -- adenosine 3′, 5′-cyclic monophosphate -- pERK -- phosphorylated extracellular regulated kinase -- IP1 -- inositol 1-phosphate -- Calcium-sensing receptor -- G-protein coupled receptor -- Biased signalling -- Phosphatidylinositol-specific phospholipase-C -- Adenosine 3′, 5′-cyclic monophosphate -- ERK1/2; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1016/j.febslet.2014.07.022
• Languages: English
• ISSNs: 0014-5793

Abstract

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 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 ERK1/2 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. Abstract : Intracellular loops‐2 (iL‐2) and ‐3 (iL‐3) and the proximal C‐terminus support Ca 2+ o ‐stimulated signalling. The proximal C‐terminus is not required for inhibition of adenylyl cyclase. Signalling by CaSR mutants indicates that ERK1/2 lies downstream of Gq/11 ‐PI‐PLC. iL‐2 and iL‐3 mutants demonstrate the existence of a distinct signalling pathway for Ca 2+ i mobilization. Requirements for adenylyl cyclase suppression are distinct from those for PI‐PLC stimulation.