Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 28 September 2010
Vol. 3, Issue 141, p. ec299
[DOI: 10.1126/scisignal.3141ec299]

EDITORS' CHOICE

Cell Biology Down with TRPV4

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

β-arrestins are multifunctional adaptor proteins implicated in the down-regulation of various classes of receptors, including G protein–coupled receptors (GPCRs), atypical seven-transmembrane receptors, receptor tyrosine kinases, and receptor serine/threonine kinases. The interaction of β-arrestins with GPCRs also mediates specific downstream signals, which can be selectively triggered with biased agonists. A particular type of angiotensin receptor, AT1aR, signals both through G proteins and through β-arrestin to mediate distinct cellular responses. Previous work had identified transient receptor potential 4 (TRPV4), a nonselective cation channel implicated in heat sensing, pain signaling, and vascular regulation, in a screen for β-arrestin–interacting proteins. Shukla et al. follow up on this work and show that, in rat vascular smooth muscle cells (rVSMCs), angiotensin stimulation resulted in the transient association of β-arrestin1 with TRPV4, which was detected by coimmunoprecipitation. Overexpression of AT1aR in either the rVSMCs (to increase its abundance for detection by Western blotting) or in human embryonic kidney (HEK) 293 cells showed that AT1aR and TRPV4 colocalized (by immunofluorescence) and coimmunoprecipitated. Pretreatment of rVSMCs with angiotensin resulted in a reduction in the abundance of TRPV4 at the cell surface and reduced calcium influx in response to a specific TRPV4 agonist (4-{alpha}-PDD). A β-arrestin signaling-biased ligand also reduced the response to 4-{alpha}-PDD, and knockdown of β-arrestin1, but not β-arrestin2, blocked the reduction in TRPV4 at the cell surface and the reduction in the response to 4-{alpha}-PDD. Stimulation of rVSMCs with angiotensin or the β-arrestin–biased ligand resulted in the ubiquitinylation of TRPV4, which was blocked in cells in which β-arrestin1 (rVSMCs and HEK293) or the ubiquitin ligase AIP4 (HEK293) was knocked down. In addition, in rVSMCs, knockdown of AIP4 prevented the angiotensin-stimulated reduction in calcium influx in response to 4-{alpha}-PDD. Thus, β-arrestin serves to couple GPCR signaling to regulation of ion channel activity.

A. K. Shukla, J. Kim, S. Ahn, K. Xiao, S. K. Shenoy, W. Liedtke, R. J. Lefkowitz, Arresting a transcript receptor potential (TRP) channel: β-arrestin 1 mediates ubiquitination and functional down-regulation of TRPV4. J. Biol. Chem. 285, 30115–30125 (2010). [Abstract] [Full Text]

Citation: N. R. Gough, Down with TRPV4. Sci. Signal. 3, ec299 (2010).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882