Arresting a Transient Receptor Potential (TRP) Channel β-ARRESTIN 1 MEDIATES UBIQUITINATION AND FUNCTIONAL DOWN-REGULATION OF TRPV4

beta-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 crosstalk 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 Ca2+ concentration to avoid excessive Ca2+ signaling.