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

Logo for

J. Biol. Chem. 285 (39): 30115-30125

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Arresting a Transient Receptor Potential (TRP) Channel

β-ARRESTIN 1 MEDIATES UBIQUITINATION AND FUNCTIONAL DOWN-REGULATION OF TRPV4*Formula {diamondsuit}

Arun K. Shukla{ddagger}§12, Jihee Kim{ddagger}1, Seungkirl Ahn{ddagger}, Kunhong Xiao{ddagger}, Sudha K. Shenoy{ddagger}, Wolfgang Liedtke{ddagger}, , and Robert J. Lefkowitz{ddagger}§3

From the Departments of {ddagger}Medicine and
Neurobiology and
the §Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710

ABSTRACT Back to Top

Abstract: β-Arrestins, originally discovered to desensitize activated G protein-coupled receptors, (aka seven-transmembrane receptors, 7TMRs) also mediate 7TMR internalization and G protein-independent signaling via these receptors. More recently, several regulatory roles of β-arrestins for atypical 7TMRs and non-7TM receptors have emerged. Here, we uncover an entirely novel regulatory role of β-arrestins in cross-talk between the angiotensin receptor (AT1aR) and a member of the transient receptor potential (TRP) ion channel family, TRPV4. AT1aR and TRPV4 form a constitutive complex in the plasma membrane, and angiotensin stimulation leads to recruitment of β-arrestin 1 to this complex. Surprisingly, angiotensin stimulation results in ubiquitination of TRPV4, a process that requires β-arrestin 1, and subsequently to internalization and functional down-regulation of TRPV4. β-Arrestin 1 interacts with, and acts as an adaptor for AIP4, an E3 ubiquitin ligase responsible for TRPV4 ubiquitination. Thus, our data provide the first evidence of a functional link between β-arrestins and TRPV4 and uncovers an entirely novel mechanism to maintain appropriate intracellular Ca2+ concentration to avoid excessive Ca2+ signaling.


Key Words: Calcium • Endocytosis • G Protein-coupled Receptors (GPCR) • TRP Channels • Ubiquitination

Received for publication May 5, 2010. Revision received July 19, 2010.

FOOTNOTES Back to Top

1 These authors contributed equally to this work.

Author's Choice—Final version full access.

Creative Commons Attribution Non-Commercial License applies to Author Choice Articles

2 To whom correspondence may be addressed: 463 Carl Bldg., Research Dr., Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-4703; Fax: 919-684-8875; E-mail: arun.shukla{at}receptor-biol.duke.edu.

3 A Howard Hughes Medical Institute Investigator. To whom correspondence may be addressed: 471 Carl Bldg., Research Dr., Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001{at}receptor-biol.duke.edu.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Characterization of blood pressure and endothelial function in TRPV4-deficient mice with l-NAME- and angiotensin II-induced hypertension.
Y. Nishijima, X. Zheng, H. Lund, M. Suzuki, D. L. Mattson, and D. X. Zhang (2014)
PHY2 2, e00199
   Abstract »    Full Text »    PDF »
Distinct roles for {beta}-arrestin2 and arrestin-domain-containing proteins in {beta}2 adrenergic receptor trafficking.
S.-O. Han, R. P. Kommaddi, and S. K. Shenoy (2013)
EMBO Rep. 14, 164-171
   Abstract »    Full Text »    PDF »
{beta}-Arrestin-2 Desensitizes the Transient Receptor Potential Vanilloid 1 (TRPV1) Channel.
E. D. Por, S. M. Bierbower, K. A. Berg, R. Gomez, A. N. Akopian, W. C. Wetsel, and N. A. Jeske (2012)
J. Biol. Chem. 287, 37552-37563
   Abstract »    Full Text »    PDF »
Differential Ubiquitination and Proteasome Regulation of CaV2.2 N-Type Channel Splice Isoforms.
S. Marangoudakis, A. Andrade, T. D. Helton, S. Denome, A. J. Castiglioni, and D. Lipscombe (2012)
J. Neurosci. 32, 10365-10369
   Abstract »    Full Text »    PDF »
G Protein-Dependent and G Protein-Independent Signaling Pathways and Their Impact on Cardiac Function.
D. G. Tilley (2011)
Circ. Res. 109, 217-230
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


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