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Arresting a transient receptor potential (TRP) channel: beta-arrestin 1 mediates ubiquitination and functional down-regulation of TRPV4 Shukla AK; Kim J; Ahn S; Xiao K; Shenoy SK; Liedtke W; Lefkowitz RJJ Biol Chem 2010[Sep]; 285 (39): 30115-25beta-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 beta-arrestins for atypical 7TMRs and non-7TM receptors have emerged. Here, we uncover an entirely novel regulatory role of beta-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 beta-arrestin 1 to this complex. Surprisingly, angiotensin stimulation results in ubiquitination of TRPV4, a process that requires beta-arrestin 1, and subsequently to internalization and functional down-regulation of TRPV4. beta-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 beta-arrestins and TRPV4 and uncovers an entirely novel mechanism to maintain appropriate intracellular Ca(2+) concentration to avoid excessive Ca(2+) signaling.|Angiotensins/pharmacology[MESH]|Animals[MESH]|Arrestins/genetics/*metabolism[MESH]|Calcium/metabolism[MESH]|Cell Line[MESH]|Humans[MESH]|Multiprotein Complexes/genetics/metabolism[MESH]|Rats[MESH]|Receptor, Angiotensin, Type 1/genetics/metabolism[MESH]|Repressor Proteins/genetics/metabolism[MESH]|TRPV Cation Channels/genetics/*metabolism[MESH]|Ubiquitin-Protein Ligases/genetics/metabolism[MESH]|Ubiquitination/drug effects/*physiology[MESH]|beta-Arrestin 1[MESH]|beta-Arrestins[MESH] |
