دورية أكاديمية
أعرض في EDS

Unique Positive Cooperativity Between the β -Arrestin-Biased β -Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the β 2-Adrenergic Receptor.

التفاصيل البيبلوغرافية
العنوان: Unique Positive Cooperativity Between the β -Arrestin-Biased β -Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the β 2-Adrenergic Receptor.
المؤلفون: Pani B; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Ahn S; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Rambarat PK; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Vege S; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Kahsai AW; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Liu A; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Valan BN; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Staus DP; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Costa T; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.)., Lefkowitz RJ; Department of Medicine (B.P., S.A., S.V., A.W.K., A.L., B.N.V., D.P.S., R.J.L.), Department of Biochemistry (R.J.L.), and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA (P.K.R.); and Viale America 111, Rome, Italy (T.C.) lefko001@receptor-biol.duke.edu.
المصدر: Molecular pharmacology [Mol Pharmacol] 2021 Nov; Vol. 100 (5), pp. 513-525. Date of Electronic Publication: 2021 Sep 27.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics
مواضيع طبية MeSH: Receptors, Adrenergic, beta-2*/metabolism, Adrenergic beta-Antagonists/*pharmacology , Carvedilol/*pharmacology , beta-Arrestins/*pharmacology, Adrenergic beta-Antagonists/chemistry ; Adrenergic beta-Antagonists/metabolism ; Allosteric Regulation/drug effects ; Allosteric Regulation/physiology ; Animals ; Carvedilol/chemistry ; Carvedilol/metabolism ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Sf9 Cells ; beta-Arrestins/chemistry ; beta-Arrestins/metabolism
مستخلص: Among β -blockers that are clinically prescribed for heart failure, carvedilol is a first-choice agent with unique pharmacological properties. Carvedilol is distinct from other β -blockers in its ability to elicit β -arrestin-biased agonism, which has been suggested to underlie its cardioprotective effects. Augmenting the pharmacologic properties of carvedilol thus holds the promise of developing more efficacious and/or biased β -blockers. We recently identified compound-6 (cmpd-6), the first small molecule positive allosteric modulator of the β 2-adrenergic receptor ( β 2AR). Cmpd-6 is positively cooperative with orthosteric agonists at the β 2AR and enhances agonist-mediated transducer (G-protein and β -arrestin) signaling in an unbiased manner. Here, we report that cmpd-6, quite unexpectedly, displays strong positive cooperativity only with carvedilol among a panel of structurally diverse β -blockers. Cmpd-6 enhances the binding affinity of carvedilol for the β 2AR and augments its ability to competitively antagonize agonist-induced cAMP generation. Cmpd-6 potentiates β -arrestin1- but not Gs-protein-mediated high-affinity binding of carvedilol at the β 2AR and β -arrestin-mediated cellular functions in response to carvedilol including extracellular signal-regulated kinase phosphorylation, receptor endocytosis, and trafficking into lysosomes. Importantly, an analog of cmpd-6 that selectively retains positive cooperativity with carvedilol acts as a negative modulator of agonist-stimulated β 2AR signaling. These unprecedented cooperative properties of carvedilol and cmpd-6 have implications for fundamental understanding of G-protein-coupled receptor (GPCR) allosteric modulation, as well as for the development of more effective biased beta blockers and other GPCR therapeutics. SIGNIFICANCE STATEMENT: This study reports on the small molecule-mediated allosteric modulation of the β -arrestin-biased β -blocker, carvedilol. The small molecule, compound-6 (cmpd-6), displays an exclusive positive cooperativity with carvedilol among other β -blockers and enhances the binding affinity of carvedilol for the β 2-adrenergic receptor. Cooperative effects of cmpd-6 augment the β -blockade property of carvedilol while potentiating its β -arrestin-mediated signaling functions. These findings have potential implications in advancing G-protein-coupled receptor allostery, developing biased therapeutics and remedying cardiovascular ailments.
(U.S. Government work not protected by U.S. copyright.)
التعليقات: Erratum in: Mol Pharmacol. 2021 Dec;100(6):597. (PMID: 34862306)
References: Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):3834-3839. (PMID: 29581292)
Sci Signal. 2018 Sep 25;11(549):. (PMID: 30254056)
Nature. 2013 May 2;497(7447):137-41. (PMID: 23604254)
Nature. 2011 Jan 13;469(7329):175-80. (PMID: 21228869)
Science. 2019 Jun 28;364(6447):1283-1287. (PMID: 31249059)
JAMA. 2002 Feb 20;287(7):883-9. (PMID: 11851582)
Trends Mol Med. 2004 Feb;10(2):55-8. (PMID: 15106619)
Mol Pharmacol. 2014 Nov;86(5):463-78. (PMID: 25061106)
Dev Cell. 2009 Oct;17(4):443-58. (PMID: 19853559)
Nat Rev Drug Discov. 2013 Aug;12(8):630-44. (PMID: 23903222)
Nat Rev Mol Cell Biol. 2018 Oct;19(10):638-653. (PMID: 30104700)
Nat Commun. 2017 Nov 22;8(1):1706. (PMID: 29167435)
Mol Pharmacol. 2018 Aug;94(2):850-861. (PMID: 29769246)
Circulation. 1996 Dec 1;94(11):2807-16. (PMID: 8941106)
Trends Pharmacol Sci. 2011 Sep;32(9):521-33. (PMID: 21680031)
Expert Rev Cardiovasc Ther. 2006 May;4(3):417-32. (PMID: 16716102)
Nature. 2016 Jul 7;535(7610):182-6. (PMID: 27362234)
Nature. 2018 Jul;559(7712):45-53. (PMID: 29973731)
J Biol Chem. 1999 Nov 5;274(45):32248-57. (PMID: 10542263)
J Biol Chem. 2015 Aug 7;290(32):19478-88. (PMID: 26100627)
Curr Opin Cell Biol. 2014 Apr;27:18-24. (PMID: 24680426)
Nat Chem Biol. 2011 Aug 21;7(10):692-700. (PMID: 21857662)
Science. 2012 Mar 2;335(6072):1106-10. (PMID: 22267580)
Anal Biochem. 1995 Oct 10;231(1):269-71. (PMID: 8678314)
N Engl J Med. 1996 May 23;334(21):1349-55. (PMID: 8614419)
Sci Signal. 2018 Aug 21;11(544):. (PMID: 30131371)
Annu Rev Pharmacol Toxicol. 2012;52:179-97. (PMID: 21942629)
Circ Res. 2018 Aug 31;123(6):716-735. (PMID: 30355236)
J Biol Chem. 2014 May 16;289(20):14211-24. (PMID: 24668815)
Trends Mol Med. 2011 Mar;17(3):126-39. (PMID: 21183406)
Nature. 2002 Jan 10;415(6868):206-12. (PMID: 11805844)
Nature. 2011 Jul 19;477(7366):549-55. (PMID: 21772288)
J Clin Invest. 2007 Sep;117(9):2445-58. (PMID: 17786238)
Biophys J. 2004 Jun;86(6):3993-4003. (PMID: 15189895)
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14555-60. (PMID: 18787115)
Nat Rev Drug Discov. 2018 Apr;17(4):243-260. (PMID: 29302067)
Science. 2007 Nov 23;318(5854):1258-65. (PMID: 17962520)
Nature. 2016 Jul 21;535(7612):448-52. (PMID: 27409812)
Recent Prog Horm Res. 1996;51:319-51; discussion 352-3. (PMID: 8701085)
Circulation. 1996 Dec 1;94(11):2800-6. (PMID: 8941105)
IUCrJ. 2019 Oct 24;6(Pt 6):1106-1119. (PMID: 31709066)
Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12435-12443. (PMID: 32414934)
Nature. 2017 Aug 24;548(7668):480-484. (PMID: 28813418)
Annu Rev Pharmacol Toxicol. 1999;39:343-60. (PMID: 10331088)
Acta Physiol (Oxf). 2007 May;190(1):9-19. (PMID: 17428228)
J Cell Biol. 2012 Nov 26;199(5):817-30. (PMID: 23166351)
Nature. 2010 Jan 7;463(7277):108-12. (PMID: 20054398)
Anal Biochem. 1999 Nov 1;275(1):74-83. (PMID: 10542111)
Mol Pharmacol. 2021 Dec;100(6):568-579. (PMID: 34561298)
Cell. 2015 May 21;161(5):1101-1111. (PMID: 25981665)
Nat Struct Mol Biol. 2018 Jan;25(1):4-12. (PMID: 29323277)
Nature. 2013 Oct 24;502(7472):575-579. (PMID: 24056936)
Trends Pharmacol Sci. 2007 Aug;28(8):397-406. (PMID: 17629961)
Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1708-1713. (PMID: 28130548)
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62. (PMID: 17925438)
معلومات مُعتمدة: R01 HL016037 United States HL NHLBI NIH HHS; United States HHMI Howard Hughes Medical Institute
المشرفين على المادة: 0 (Adrenergic beta-Antagonists)
0 (Receptors, Adrenergic, beta-2)
0 (beta-Arrestins)
0K47UL67F2 (Carvedilol)
تواريخ الأحداث: Date Created: 20210928 Date Completed: 20211110 Latest Revision: 20220716
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC8998675
DOI: 10.1124/molpharm.121.000363
PMID: 34580163
قاعدة البيانات: MEDLINE
الوصف
تدمد:1521-0111
DOI:10.1124/molpharm.121.000363