Arresting a transient receptor potential (TRP) channel: beta-arrestin 1 mediates ubiquitination and functional down-regulation of TRPV4.
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 Ca(2+) concentration to avoid excessive Ca(2+) signaling.
Shukla
Arun K
AK
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kim
Jihee
J
Ahn
Seungkirl
S
Xiao
Kunhong
K
Shenoy
Sudha K
SK
Liedtke
Wolfgang
W
Lefkowitz
Robert J
RJ
D000809:Angiotensins / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology*; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D000809:Angiotensins; C000605256:Arrb1 protein, rat; D019390:Arrestins; D046912:Multiprotein Complexes; D044140:Receptor, Angiotensin, Type 1; D012097:Repressor Proteins; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486577:Trpv4 protein, rat; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D002118:Calcium