title: β-arrestin1-biased β1-adrenergic receptor signaling regulates microRNA processing.
abstract: BACKGROUND
  MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin intermediate miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes after 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.
  
  
  OBJECTIVE
  Here, we tested whether carvedilol could activate β-arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects.
  
  
  RESULTS
  In human cells and mouse hearts, carvedilol upregulates a subset of mature and pre-miRs, but not their pri-miRs, in β1AR-, G-protein-coupled receptor kinase 5/6-, and β-arrestin1-dependent manner. Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs.
  
  
  CONCLUSIONS
  Our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.
authors: From Vascular Biology Center (I.K., Y.W., K.P., Y.T., J.T., H.S.), Department of Biochemistry and Molecular Biology (I.K.), Medical College of Georgia (I.K., J.V.), and Department of Pharmacology and Toxicology (H.S., J.A.J.), Georgia Regents University, Augusta, GA; Center for Translational Medicine (C.J.T., W.J.K.), and Department of Pharmacology (W.J.K.), Temple University School of Medicine, Philadelphia, PA; and Department of Medicine (G.P., L.M., H.A.R.), Cell Biology (H.A.R.), and Molecular Genetics (H.A.R.), Duke University Medical Center, Durham, NC.
authors: Il-Man
authors: IM
authors: Kim
authors: Yongchao
authors: Y
authors: Wang
authors: Kyoung-Mi
authors: KM
authors: Park
authors: Yaoping
authors: Y
authors: Tang
authors: Jian-Peng
authors: JP
authors: Teoh
authors: Joseph
authors: J
authors: Vinson
authors: Christopher J
authors: CJ
authors: Traynham
authors: Gianluigi
authors: G
authors: Pironti
authors: Lan
authors: L
authors: Mao
authors: Huabo
authors: H
authors: Su
authors: John A
authors: JA
authors: Johnson
authors: Walter J
authors: WJ
authors: Koch
authors: Howard A
authors: HA
authors: Rockman
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000378:metabolism; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000071557:beta-Arrestins
chemical_list: C547787:ADRB1 protein, human; C547788:Adrb1 protein, mouse; D058665:Adrenergic beta-1 Receptor Agonists; D019390:Arrestins; D002227:Carbazoles; C576613:MIRN190 microRNA, human; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; C529101:Mirn150 microRNA, mouse; C534781:Mirn214 microRNA, mouse; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D000071557:beta-Arrestins; D000077261:Carvedilol; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; C517898:GRK5 protein, human
keywords: carvedilol; heart diseases