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First published online 10 July 2007
doi: 10.1242/jcs.03469

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The calcium-sensing receptor changes cell shape via a -arrestin-1–ARNO–ARF6–ELMO protein network

Tristan Bouschet^1,*, Stéphane Martin¹, Venkateswarlu Kanamarlapudi^2,, Stuart Mundell² and Jeremy M. Henley^1,

¹ Department of Anatomy, MRC Centre for Synaptic Plasticity, University of Bristol, University Walk, Bristol, BS8 1TD, UK
² Department of Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK

Author for correspondence (e-mail: j.m.henley{at}bristol.ac.uk)

Accepted 27 April 2007

G-protein-coupled receptors (GPCRs) transduce the binding of extracellular stimuli into intracellular signalling cascades that can lead to morphological changes. Here, we demonstrate that stimulation of the calcium-sensing receptor (CaSR), a GPCR that promotes chemotaxis by detecting increases in extracellular calcium, triggers plasma membrane (PM) ruffling via a pathway that involves -arrestin 1, Arf nucleotide binding site opener (ARNO), ADP-ribosylating factor 6 (ARF6) and engulfment and cell motility protein (ELMO). Expression of dominant negative -arrestin 1 or its knockdown with siRNA impaired the CaSR-induced PM ruffling response. Expression of a catalytically inactive ARNO also reduced CaSR-induced PM ruffling. Furthermore, -arrestin 1 co-immunoprecipitated with the CaSR and ARNO under resting conditions. Agonist treatment did not markedly alter -arrestin 1 binding to the CaSR or to ARNO but it did elicit the translocation and colocalisation of the CaSR, -arrestin 1 and ARNO to membrane protrusions. Furthermore, ARF6 and ELMO, two proteins known to couple ARNO to the cytoskeleton, were required for CaSR-dependent morphological changes and translocated to the PM ruffles. These data suggest that cells ruffle upon CaSR stimulation via a mechanism that involves translocation of -arrestin 1 pre-assembled with the CaSR or ARNO, and that ELMO plays an essential role in this CaSR-signalling-induced cytoskeletal reorganisation.

Key words: Calcium-sensing receptor, Cytoskeleton, -arrestin 1, ARF6, ARNO, ELMO

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