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1 Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom
2 Cardiff School of Biosciences, University of Cardiff, Cardiff, United Kingdom
* To whom correspondence should be addressed. E-mail: d.ward{at}manchester.ac.uk.
The calcium-sensing receptor (CaR) is a pleiotropic, type III GPCR that associates functionally with the cytoskeletal protein filamin. To investigate the effect of CaR signaling on the cytoskeleton, HEK-293 cells stably transfected with CaR (CaR-HEK) were incubated with CaR agonists in serum-free medium for up to 3-hours. The calcimimetic NPS-467R or exposure to high extracellular Ca2+ or Mg2+ levels elicited actin stress fiber assembly and process retraction in otherwise stellate cells. These responses were ablated by cotreatment with the calcilytic NPS-89636 and were absent in vector-transfected HEK cells. Cotreatment with the rho-kinase inhibitors Y27632 and H1152 attenuated the CaR-induced morphological change but not Ca2+i mobilization or ERK activation, whilst transfection with a dominant-negative RhoA binding protein also inhibited calcimimetic-induced actin stress fiber assembly. The CaR effects on morphology were unaffected by inhibition of Gq/11 or Gi/o signaling, EGF receptor or the metalloproteinases. In contrast, CaR-induced cytoskeletal changes were not induced by the aromatic amino acids, treatments that also failed to potentiate CaR-induced ERK activation, despite their inducing Ca2+i mobilization. Together, these data establish that the CaR can elicit rho-mediated changes in stress fiber assembly and cell morphology, effects that could contribute towards the receptors physiological actions. In addition, this study provides further evidence that aromatic amino acids elicit differential signaling from other CaR agonists.
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