Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Biol Chem. 2010 Sep 24;285(39):30115-25. doi: 10.1074/jbc.M110.141549. Epub 2010 Jul 22.
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.
β-arrestins 最初被发现可使激活的 G 蛋白偶联受体脱敏（也称为七跨膜受体，7TMRs），还可通过这些受体介导 7TMR 内化和 G 蛋白非依赖性信号转导。最近，β-arrestins 对非典型 7TMRs 和非 7TM 受体的几种调节作用也已显现。在这里，我们揭示了β-arrestins 在血管紧张素受体（AT1aR）和瞬时受体电位（TRP）离子通道家族成员 TRPV4 之间相互作用的全新调节作用。AT1aR 和 TRPV4 在质膜中形成组成型复合物，血管紧张素刺激导致β-arrestin 1 募集到该复合物。令人惊讶的是，血管紧张素刺激导致 TRPV4 的泛素化，这一过程需要β-arrestin 1，随后 TRPV4 内化和功能下调。β-arrestin 1 与 AIP4 相互作用，并作为其衔接蛋白发挥作用，AIP4 是一种负责 TRPV4 泛素化的 E3 泛素连接酶。因此，我们的数据首次提供了β-arrestins 与 TRPV4 之间功能联系的证据，并揭示了一种全新的机制，可维持适当的细胞内 Ca（2+）浓度以避免过度的 Ca（2+）信号转导。
