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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


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.


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}

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}

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