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Projects / Project 11 - Ligand-biased G-protein activation by CaSR
 
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  • Project 1 - CaSR-mediated signalling in colonocytes
  • Project 2 - Evaluation of CaSR - based therapeutics in prevention of tumourigenesis and metastatic potential in colorectal cancer
  • Project 3 - Role of the CaSR in inflammatory lung diseases
  • Project 4 - Evaluation of CaSR-targeted drugs for the treatment of neuroblastoma
  • Project 5 - Delineation of CaSR signalling in primary cells and cell lines with native receptor expression
  • Project 6 - Role of the calcium-sensing receptor (CaSR) in glucose homeostasis
  • Project 7 - Cell-specific CaSR signaling
  • Project 8 - Targeting CaSR in human skeletal muscle cells to delay sarcopenia development
  • Project 9 - Evaluation of CaSR-targeted drugs for the treatment of diabetes mellitus
  • Project 10 - Role of the CaSR in early bone metastasis of breast cancer cells and evaluation of CaSR - based therapeutics in prevention or delay of metastasis formation
  • Project 11 - Ligand-biased G-protein activation by CaSR
  • Project 12 - The role of CaSR in AD pathomechanisms
  • Project 13 - In silico analysis of CaSR-ligand interaction
  • Project 14 -Generation, validation and application of algorithms for tissue segmentation used in advanced tissue cytometry


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Project 11 - Ligand-biased G-protein activation by CaSR

Host Institution: Stichting VU-VUMC
» Info

Hypothesis: CaSR is believed to activate three different G-proteins in a ligand-combination dependent manner. So far, this has been indirectly inferred from downstream signalling activation, such as ERK, cAMP, and intracellular calcium oscillations. A second hypothesis is that the intracellular signalling state can (de-)sensitize CaSR for extracellular signals, for instance via its phosphorylation by PKC.

Objectives: To study ligand-biased activation of Gq and Gi by the CaSR as function of Ca2+o, and allosteric modifiers at the level of single cells using G-protein sensors (Gq and Gi) to track receptor decisions at the membrane (AIM 1). These experiments will be carried out as function of the modulation of intracellular signalling processes, such as PKC and PP2A that are known to be involved in the phosphorylation of CaSR, to investigate whether the cellular signalling state can (de-)sensitize the receptor (AIM 2). To reach those objectives, ESRVU will perform experiments using Gq & Gi FRET sensors using the same cell lines as ESRUM. Mathematical modelling of CaSR signalling based on the results of ESRVU, ESRUM, ESRMUW1 will be done to integrate data.

 
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