6u1n

Structural highlights

Disease

[ACM2_HUMAN] Disease susceptibility is associated with variations affecting the gene represented in this entry.

Function

[ACM2_HUMAN] The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. [ARRB1_RAT] Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]}

References

1. ↑ Ferguson SS, Downey WE 3rd, Colapietro AM, Barak LS, Menard L, Caron MG. Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science. 1996 Jan 19;271(5247):363-6. PMID:8553074
2. ↑ Lin FT, Krueger KM, Kendall HE, Daaka Y, Fredericks ZL, Pitcher JA, Lefkowitz RJ. Clathrin-mediated endocytosis of the beta-adrenergic receptor is regulated by phosphorylation/dephosphorylation of beta-arrestin1. J Biol Chem. 1997 Dec 5;272(49):31051-7. PMID:9388255
3. ↑ Lin FT, Daaka Y, Lefkowitz RJ. beta-arrestins regulate mitogenic signaling and clathrin-mediated endocytosis of the insulin-like growth factor I receptor. J Biol Chem. 1998 Nov 27;273(48):31640-3. PMID:9822622
4. ↑ Vogler O, Nolte B, Voss M, Schmidt M, Jakobs KH, van Koppen CJ. Regulation of muscarinic acetylcholine receptor sequestration and function by beta-arrestin. J Biol Chem. 1999 Apr 30;274(18):12333-8. PMID:10212203
5. ↑ Barlic J, Khandaker MH, Mahon E, Andrews J, DeVries ME, Mitchell GB, Rahimpour R, Tan CM, Ferguson SS, Kelvin DJ. beta-arrestins regulate interleukin-8-induced CXCR1 internalization. J Biol Chem. 1999 Jun 4;274(23):16287-94. PMID:10347185
6. ↑ Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science. 1999 Jan 29;283(5402):655-61. PMID:9924018
7. ↑ Bremnes T, Paasche JD, Mehlum A, Sandberg C, Bremnes B, Attramadal H. Regulation and intracellular trafficking pathways of the endothelin receptors. J Biol Chem. 2000 Jun 9;275(23):17596-604. PMID:10747877 doi:10.1074/jbc.M000142200
8. ↑ DeFea KA, Zalevsky J, Thoma MS, Dery O, Mullins RD, Bunnett NW. beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol. 2000 Mar 20;148(6):1267-81. PMID:10725339
9. ↑ DeFea KA, Vaughn ZD, O'Bryan EM, Nishijima D, Dery O, Bunnett NW. The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta -arrestin-dependent scaffolding complex. Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11086-91. PMID:10995467 doi:10.1073/pnas.190276697
10. ↑ Chen W, Hu LA, Semenov MV, Yanagawa S, Kikuchi A, Lefkowitz RJ, Miller WE. beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14889-94. Epub 2001 Dec 11. PMID:11742073 doi:10.1073/pnas.211572798
11. ↑ Qian H, Pipolo L, Thomas WG. Association of beta-Arrestin 1 with the type 1A angiotensin II receptor involves phosphorylation of the receptor carboxyl terminus and correlates with receptor internalization. Mol Endocrinol. 2001 Oct;15(10):1706-19. PMID:11579203
12. ↑ Tohgo A, Pierce KL, Choy EW, Lefkowitz RJ, Luttrell LM. beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation. J Biol Chem. 2002 Mar 15;277(11):9429-36. Epub 2002 Jan 2. PMID:11777902 doi:10.1074/jbc.M106457200
13. ↑ Goel R, Phillips-Mason PJ, Raben DM, Baldassare JJ. alpha-Thrombin induces rapid and sustained Akt phosphorylation by beta-arrestin1-dependent and -independent mechanisms, and only the sustained Akt phosphorylation is essential for G1 phase progression. J Biol Chem. 2002 May 24;277(21):18640-8. Epub 2002 Mar 18. PMID:11901145 doi:10.1074/jbc.M108995200
14. ↑ Perry SJ, Baillie GS, Kohout TA, McPhee I, Magiera MM, Ang KL, Miller WE, McLean AJ, Conti M, Houslay MD, Lefkowitz RJ. Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science. 2002 Oct 25;298(5594):834-6. PMID:12399592 doi:10.1126/science.1074683
15. ↑ Iacovelli L, Salvatore L, Capobianco L, Picascia A, Barletta E, Storto M, Mariggio S, Sallese M, Porcellini A, Nicoletti F, De Blasi A. Role of G protein-coupled receptor kinase 4 and beta-arrestin 1 in agonist-stimulated metabotropic glutamate receptor 1 internalization and activation of mitogen-activated protein kinases. J Biol Chem. 2003 Apr 4;278(14):12433-42. Epub 2003 Jan 7. PMID:12519791 doi:10.1074/jbc.M203992200
16. ↑ Ge L, Ly Y, Hollenberg M, DeFea K. A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis. J Biol Chem. 2003 Sep 5;278(36):34418-26. Epub 2003 Jun 23. PMID:12821670 doi:10.1074/jbc.M300573200
17. ↑ Witherow DS, Garrison TR, Miller WE, Lefkowitz RJ. beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8603-7. Epub 2004 Jun 1. PMID:15173580 doi:10.1073/pnas.0402851101
18. ↑ Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O. {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem. 2005 Jul 1;280(26):24412-9. Epub 2005 May 3. PMID:15878855 doi:10.1074/jbc.M501129200
19. ↑ Huet E, Boulay F, Barral S, Rabiet MJ. The role of beta-arrestins in the formyl peptide receptor-like 1 internalization and signaling. Cell Signal. 2007 Sep;19(9):1939-48. Epub 2007 May 29. PMID:17594911 doi:10.1016/j.cellsig.2007.05.006
20. ↑ Lee MH, El-Shewy HM, Luttrell DK, Luttrell LM. Role of beta-arrestin-mediated desensitization and signaling in the control of angiotensin AT1a receptor-stimulated transcription. J Biol Chem. 2008 Jan 25;283(4):2088-97. Epub 2007 Nov 15. PMID:18006496 doi:10.1074/jbc.M706892200
21. ↑ Staus DP, Hu H, Robertson MJ, Kleinhenz ALW, Wingler LM, Capel WD, Latorraca NR, Lefkowitz RJ, Skiniotis G. Structure of the M2 muscarinic receptor-beta-arrestin complex in a lipid nanodisc. Nature. 2020 Jan 16. pii: 10.1038/s41586-020-1954-0. doi:, 10.1038/s41586-020-1954-0. PMID:31945772 doi:http://dx.doi.org/10.1038/s41586-020-1954-0