β-Arrestin2, a novel member of the arrestin/β-arrestin gene family
Homologous or agonist-specific desensitization of β2-adrenergic receptors (β2AR) is mediated by the β-adrenergic receptor kinase (βARK) which specifically phosphorylates the agonist-occupied form of the receptor. However, the capacity of βARK-phosphorylated β2AR to stimulate G(s) in a reconstituted system is only minimally impaired. Recently, a protein termed β-arrestin, was cloned from a bovine brain cDNA library and found to quench phosphorylated β2AR-coupling to G(s). Utilizing a low stringency hybridization technique to screen a rat brain cDNA library, we have now isolated cDNA clones representing two distinct β-arrestin-like genes. One of the cDNAs is the rat homolog of bovine β-arrestin (β-arrestin1). In addition, we have isolated a cDNA clone encoding a novel, β-arrestin-related protein which we have termed β-arrestin2. Overall, β-arrestin2 exhibits 78% amino acid identity with β-arrestin1. The primary structure of these proteins delineates a family of proteins that regulates receptor coupling to G proteins. The capacity of purified β-arrestin1, β-arrestin2, and arrestin to inhibit the coupling of phosphorylated receptors to their respective G proteins were assessed in a reconstituted β2AR-G(s) system and in a reconstituted rhodopsin-G(T) system. β-Arrestin2 was equipotent to β- arrestin1 and specifically inhibited β2AR function. Conversely, arrestin inhibited rhodopsin coupling to G(T), whereas β-arrestin1 and β-arrestin2 were at least 20-fold less potent in this system. β-Arrestin1 and β- arrestin2 are predominantly localized in neuronal tissues and in the spleen. However, low mRNA levels can be detected in most peripheral tissues. In the central nervous system, β-arrestin2 appears to be even more abundant than β-arrestin1. Immunohistochemical analysis of the tissue distribution of β- arrestin1 and β-arrestin2 in rat brain shows extensive, but heterogenous, neuronal labeling of the two proteins. They are found in several neuronal pathways suggesting that they have relatively broad receptor specificity regulating many G protein-coupled receptors. Furthermore, immunoelectron microscopy shows that the β-arrestins are appropriately situated at postsynaptic sites to act in concert with βARK to regulate G protein-coupled neurotransmitter receptors.
Attramadal, H; Arriza, JL; Aoki, C; Dawson, TM; Codina, J; Kwatra, MM; Snyder, SH; Caron, MG; Lefkowitz, RJ
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