MicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary transcripts (pri-miRs), they are processed in the nucleus by Drosha into hairpin intermediates (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes following activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-arrestins are now appreciated to transduce multiple effector pathways independent of G protein-mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the β-arrestin-biased βAR agonist carvedilol activates cellular pathways in the heart. Here, we tested the hypothesis that carvedilol could activate β-arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects. In human cells and mouse hearts, carvedilol (Carv) upregulates a subset of mature and pre-miRs but not their pri-miRs in a β1AR-, G protein-coupled receptor kinase (GRK) 5/6- and β-arrestin1-dependent manner (see figure). Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1, a component of the Drosha microprocessor complex (see figure). In conclusion, our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling in miR biogenesis, which may be linked to its cell survival mechanism and beneficial adaptive remodeling in the failing heart.
Biased Coupling to β-Arrestin of Two Common Variants of the CB2 Cannabinoid Receptor
