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Background  Sustained agonist-promoted ubiquitination of β-arrestin has been correlated with increased stability of the GPCR – β-arrestin complex. Moreover, abrogation of β-arrestin ubiquitination has been reported to inhibit receptor internalization with minimal effects on receptor degradation.    Results  Herein we report that agonist activation of M 1  mAChRs produces a sustained β-arrestin ubiquitination but no stable co-localization with β-arrestin. In contrast, sustained ubiquitination of β-arrestin by activation of M 2  mAChRs does result in stable co-localization between the M 2  mAChR and β-arrestin. Internalization of receptors was unaffected by proteasome inhibitors, but down-regulation was significantly reduced, suggesting a role for the ubiquitination machinery in promoting down-regulation of the receptors. Given the ubiquitination status of β-arrestin following agonist treatment, we sought to determine the effects of β-arrestin ubiquitination on M 1  and M 2  mAChR down-regulation. A constitutively ubiquitinated β-arrestin 2 chimera in which ubiquitin is fused to the C-terminus of β-arrestin 2 (YFP-β-arrestin 2-Ub) significantly increased agonist-promoted down-regulation of both M 1  and M 2  mAChRs, with the effect substantially higher on the M 2  mAChR. Based on this observation, we were interested in examining the effects of disruption of potential ubiquitination sites in the β-arrestin sequence on receptor down-regulation. Agonist-promoted internalization of the M 2  mAChR was not affected by expression of β-arrestin lysine mutants lacking putative ubiquitination sites, β-arrestin 2 K18R, K107R, K108R, K207R, K296R , while down-regulation and stable co-localiztion of the receptor with this β-arrestin lysine mutant were significantly reduced. Interestingly, expression of β-arrestin 2 K18R, K107R, K108R, K207R, K296R  increased the agonist-promoted down-regulation of the M 1  mAChR but did not result in a stable co-localiztion of the receptor with this β-arrestin lysine mutant.    Conclusion  These findings indicate that ubiquitination of β-arrestin has a distinct role in the differential trafficking and degradation of M 1  and M 2  mAChRs.

journal of molecular signaling

Differential role of beta-arrestin ubiquitination in agonist-promoted down-regulation of M&lt;sub&gt;1&lt;/sub&gt; &lt;em&gt;vs&lt;/em&gt; M&lt;sub&gt;2&lt;/sub&gt; muscarinic acetylcholine receptors