1932

Abstract

Formation of signaling complexes is crucial for the orchestration of fast, efficient, and specific signal transduction. Pharmacological disruption of defined signaling complexes has the potential for specific intervention in selected regulatory pathways without affecting organism-wide disruption of parallel pathways. Signaling by epinephrine and norepinephrine through α and β adrenergic receptors acts on many signaling pathways in many cell types. Here, we initially provide an overview of the signaling complexes formed between the paradigmatic β adrenergic receptor and two of its most important targets, the L-type Ca2+ channel Ca1.2 and the AMPA-type glutamate receptor. Importantly, both complexes contain the trimeric G protein, adenylyl cyclase, and the cAMP-dependent protein kinase, PKA. We then discuss the functional implications of the formation of these complexes, how those complexes can be specifically disrupted, and how such disruption could be utilized in the pharmacological treatment of disease.

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2020-01-06
2024-04-19
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Literature Cited

  1. 1. 
    Dai S, Hall DD, Hell JW 2009. Supramolecular assemblies and localized regulation of voltage-gated ion channels. Physiol. Rev. 89:411–52
    [Google Scholar]
  2. 2. 
    Langeberg LK, Scott JD. 2015. Signalling scaffolds and local organization of cellular behaviour. Nat. Rev. Mol. Cell Biol. 16:232–44
    [Google Scholar]
  3. 3. 
    Chaturvedi M, Schilling J, Beautrait A, Bouvier M, Benovic JL, Shukla AK 2018. Emerging paradigm of intracellular targeting of G protein-coupled receptors. Trends Biochem. Sci. 43:533–46
    [Google Scholar]
  4. 4. 
    Steinberg SF, Brunton LL. 2001. Compartmentation of G protein-coupled signaling pathways in cardiac myocytes. Annu. Rev. Pharmacol. Toxicol. 41:751–73
    [Google Scholar]
  5. 5. 
    Patriarchi T, Buonarati OR, Hell JW 2018. Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca2+/CaMKII signaling. EMBO J 37:e99771
    [Google Scholar]
  6. 6. 
    Xiao RP, Cheng H, Zhou YY, Kuschel M, Lakatta EG 1999. Recent advances in cardiac β2-adrenergic signal transduction. Circ. Res. 85:1092–100
    [Google Scholar]
  7. 7. 
    Davare MA, Avdonin V, Hall DD, Peden EM, Burette A et al. 2001. A β2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2. Science 293:98–101 Erratum. 2001. Science 293(5531):804
    [Google Scholar]
  8. 8. 
    Balijepalli RC, Foell JD, Hall DD, Hell JW, Kamp TJ 2006. Localization of cardiac L-type Ca2+ channels to a caveolar macromolecular signaling complex is required for β2-adrenergic regulation. PNAS 103:7500–5
    [Google Scholar]
  9. 9. 
    Joiner ML, Lise MF, Yuen EY, Kam AY, Zhang M et al. 2010. Assembly of a β2-adrenergic receptor-GluR1 signalling complex for localized cAMP signalling. EMBO J 29:482–95
    [Google Scholar]
  10. 10. 
    Wang D, Govindaiah G, Liu R, De Arcangelis V, Cox CL, Xiang YK 2010. Binding of amyloid β peptide to β2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity. Faseb J 24:3511–21
    [Google Scholar]
  11. 11. 
    Wulff H, Christophersen P, Colussi P, Chandy KG, Yarov-Yarovoy V 2019. Antibodies and venom peptides: new modalities for ion channels. Nat. Rev. Drug Discov. 18:339–57
    [Google Scholar]
  12. 12. 
    Berman DE, Dudai Y. 2001. Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 291:2417–19
    [Google Scholar]
  13. 13. 
    Cahill L, Prins B, Weber M, McGaugh JL 1994. β-Adrenergic activation and memory for emotional events. Nature 371:702–4
    [Google Scholar]
  14. 14. 
    He K, Huertas M, Hong SZ, Tie X, Hell JW et al. 2015. Distinct eligibility traces for LTP and LTD in cortical synapses. Neuron 88:528–38
    [Google Scholar]
  15. 15. 
    Brookes K, Xu X, Chen W, Zhou K, Neale B et al. 2006. The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol. Psychiatry 11:934–53
    [Google Scholar]
  16. 16. 
    Lasky-Su J, Neale BM, Franke B, Anney RJ, Zhou K et al. 2008. Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B:1345–54
    [Google Scholar]
  17. 17. 
    Liberzon I, King AP, Ressler KJ, Almli LM, Zhang P et al. 2014. Interaction of the ADRB2 gene polymorphism with childhood trauma in predicting adult symptoms of posttraumatic stress disorder. JAMA Psychiatry 71:1174–82
    [Google Scholar]
  18. 18. 
    O'Dell TJ, Connor SA, Guglietta R, Nguyen PV 2015. β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus. Learn. Mem. 22:461–71
    [Google Scholar]
  19. 19. 
    Li H, Pink MD, Murphy JG, Stein A, Dell'Acqua ML, Hogan PG 2012. Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling. Nat. Struct. Mol. Biol. 19:337–45
    [Google Scholar]
  20. 20. 
    Wheeler DG, Groth RD, Ma H, Barrett CF, Owen SF et al. 2012. Cav1 and Cav2 channels engage distinct modes of Ca2+ signaling to control CREB-dependent gene expression. Cell 149:1112–24
    [Google Scholar]
  21. 21. 
    Marrion NV, Tavalin ST. 1998. Selective activation of Ca2+-activated K+ channels by co-localized Ca2+ channels in hippocampal neurons. Nature 395:900–5
    [Google Scholar]
  22. 22. 
    Berkefeld H, Sailer CA, Bildl W, Rohde V, Thumfart JO et al. 2006. BKCa-Cav channel complexes mediate rapid and localized Ca2+-activated K+ signaling. Science 314:615–20
    [Google Scholar]
  23. 23. 
    Hell JW, Westenbroek RE, Warner C, Ahlijanian MK, Prystay W et al. 1993. Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel α1 subunits. J. Cell Biol. 123:949–62
    [Google Scholar]
  24. 24. 
    Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G et al. 2004. Isoform-specific regulation of mood behavior and pancreatic β cell and cardiovascular function by L-type Ca2+ channels. J. Clin. Investig. 113:1430–39
    [Google Scholar]
  25. 25. 
    Moosmang S, Haider N, Klugbauer N, Adelsberger H, Langwieser N et al. 2005. Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory. J. Neurosci. 25:9883–92
    [Google Scholar]
  26. 26. 
    Bolshakov VY, Siegelbaum SA. 1994. Postsynaptic induction and presynaptic expression of hippocampal long-term depression. Science 264:148–52
    [Google Scholar]
  27. 27. 
    Patriarchi T, Qian H, Di Biase V, Malik ZA, Chowdhury D et al. 2016. Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the β2 adrenergic receptor. EMBO J 35:1330–45
    [Google Scholar]
  28. 28. 
    Qian H, Patriarchi T, Price JL, Matt L, Lee B et al. 2017. Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons. Sci. Signal. 10: eaaf9659
    [Google Scholar]
  29. 29. 
    Hu H, Real E, Takamiya K, Kang MG, Ledoux J et al. 2007. Emotion enhances learning via norepinephrine regulation of AMPA-receptor trafficking. Cell 131:160–73
    [Google Scholar]
  30. 30. 
    White JA, McKinney BC, John MC, Powers PA, Kamp TJ, Murphy GG 2008. Conditional forebrain deletion of the L-type calcium channel CaV1.2 disrupts remote spatial memories in mice. Learn. Mem. 15:1–5
    [Google Scholar]
  31. 31. 
    Davare MA, Hell JW. 2003. Increased phosphorylation of the neuronal L-type Ca2+ channel Cav1.2 during aging. PNAS 100:16018–23
    [Google Scholar]
  32. 32. 
    Deyo RA, Straube KT, Disterhoft JF 1989. Nimodipine facilitates associative learning in aging rabbits. Science 243:809–11
    [Google Scholar]
  33. 33. 
    Nunez-Santana FL, Oh MM, Antion MD, Lee A, Hell JW, Disterhoft JF 2014. Surface L-type Ca2+ channel expression levels are increased in aged hippocampus. Aging Cell 13:111–20
    [Google Scholar]
  34. 34. 
    Kisko TM, Braun MD, Michels S, Witt SH, Rietschel M et al. 2018. Cacna1c haploinsufficiency leads to pro-social 50-kHz ultrasonic communication deficits in rats. Dis. Model. Mech. 11: dmm034116
    [Google Scholar]
  35. 35. 
    Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P et al. 2004. CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31
    [Google Scholar]
  36. 36. 
    Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM et al. 2008. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat. Genet. 40:1056–58
    [Google Scholar]
  37. 37. 
    Nyegaard M, Demontis D, Foldager L, Hedemand A, Flint TJ et al. 2010. CACNA1C (rs1006737) is associated with schizophrenia. Mol. Psychiatry 15:119–21
    [Google Scholar]
  38. 38. 
    Green EK, Grozeva D, Jones I, Jones L, Kirov G et al. 2010. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol. Psychiatry 15:1016–22
    [Google Scholar]
  39. 39. 
    Bhat S, Dao DT, Terrillion CE, Arad M, Smith RJ et al. 2012. CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Prog. Neurobiol. 99:1–14
    [Google Scholar]
  40. 40. 
    Smoller JW. 2013. Disorders and borders: psychiatric genetics and nosology. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B:559–78
    [Google Scholar]
  41. 41. 
    Song JHT, Lowe CB, Kingsley DM 2018. Characterization of a human-specific tandem repeat associated with bipolar disorder and schizophrenia. Am. J. Hum. Genet. 103:421–30
    [Google Scholar]
  42. 42. 
    Davare MA, Dong F, Rubin CS, Hell JW 1999. The A-kinase anchor protein MAP2B and cAMP-dependent protein kinase are associated with class C L-type calcium channels in neurons. J. Biol. Chem. 274:30280–87
    [Google Scholar]
  43. 43. 
    Hall DD, Davare MA, Shi M, Allen ML, Weisenhaus M et al. 2007. Critical role of cAMP-dependent protein kinase anchoring to the L-type calcium channel Cav1.2 via A-kinase anchor protein 150 in neurons. Biochemistry 46:1635–46
    [Google Scholar]
  44. 44. 
    Oliveria SF, Dell'Acqua ML, Sather WA 2007. AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+ channel activity and nuclear signaling. Neuron 55:261–75
    [Google Scholar]
  45. 45. 
    Willoughby D, Masada N, Wachten S, Pagano M, Halls ML et al. 2010. AKAP79/150 interacts with AC8 and regulates Ca2+-dependent cAMP synthesis in pancreatic and neuronal systems. J. Biol. Chem. 285:20328–42
    [Google Scholar]
  46. 46. 
    Efendiev R, Samelson BK, Nguyen BT, Phatarpekar PV, Baameur F et al. 2010. AKAP79 interacts with multiple adenylyl cyclase (AC) isoforms and scaffolds AC5 and -6 to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. J. Biol. Chem. 285:14450–58
    [Google Scholar]
  47. 47. 
    De Jongh KS, Murphy BJ, Colvin AA, Hell JW, Takahashi M, Catterall WA 1996. Specific phosphorylation of a site in the full length form of the α1 subunit of the cardiac L-type calcium channel by adenosine 3′,5′-cyclic monophosphate-dependent protein kinase. Biochemistry 35:10392–402
    [Google Scholar]
  48. 48. 
    Nystoriak MA, Nieves-Cintron M, Patriarchi T, Buonarati OR, Prada MP et al. 2017. Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel CaV1.2 and vasoconstriction during acute hyperglycemia and diabetes. Sci. Signal. 10: eaaf9647
    [Google Scholar]
  49. 49. 
    Lemke T, Welling A, Christel CJ, Blaich A, Bernhard D et al. 2008. Unchanged β-adrenergic stimulation of cardiac L-type calcium channels in Cav1.2 phosphorylation site S1928A mutant mice. J. Biol. Chem. 283:34738–44
    [Google Scholar]
  50. 50. 
    Shen A, Nieves-Cintron M, Deng Y, Shi Q, Chowdhury D et al. 2018. Functionally distinct and selectively phosphorylated GPCR subpopulations co-exist in a single cell. Nat. Commun. 9:1050
    [Google Scholar]
  51. 51. 
    Dupre DJ, Robitaille M, Ethier N, Villeneuve LR, Mamarbachi AM, Hebert TE 2006. Seven transmembrane receptor core signaling complexes are assembled prior to plasma membrane trafficking. J. Biol. Chem. 281:34561–73
    [Google Scholar]
  52. 52. 
    Davare MA, Horne MC, Hell JW 2000. Protein phosphatase 2A is associated with class C L-type calcium channels (CaV1.2) and antagonizes channel phosphorylation by cAMP-dependent protein kinase. J. Biol. Chem. 275:39710–17
    [Google Scholar]
  53. 53. 
    Hall DD, Feekes JA, Arachchige Don AS, Shi M, Hamid J et al. 2006. Binding of protein phosphatase 2A to the L-type calcium channel Cav1.2 next to Ser1928, its main PKA site, is critical for Ser1928 dephosphorylation. Biochemistry 45:3448–59
    [Google Scholar]
  54. 54. 
    Xu H, Ginsburg KS, Hall DD, Zimmermann M, Stein IS et al. 2010. Targeting of protein phosphatases PP2A and PP2B to the C-terminus of the L-type calcium channel Cav1.2. Biochemistry 49:10298–307
    [Google Scholar]
  55. 55. 
    Tandan S, Wang Y, Wang TT, Jiang N, Hall DD et al. 2009. Physical and functional interaction between calcineurin and the cardiac L-type Ca2+ channel. Circ. Res. 105:51–60
    [Google Scholar]
  56. 56. 
    Dittmer PJ, Dell'Acqua ML, Sather WA 2014. Ca2+/calcineurin-dependent inactivation of neuronal L-type Ca2+ channels requires priming by AKAP-anchored protein kinase A. Cell Rep 7:1410–16
    [Google Scholar]
  57. 57. 
    Oliveria SF, Dittmer PJ, Youn DH, Dell'Acqua ML, Sather WA 2012. Localized calcineurin confers Ca2+-dependent inactivation on neuronal L-type Ca2+ channels. J. Neurosci. 32:15328–37
    [Google Scholar]
  58. 58. 
    Chen-Izu Y, Xiao R-P, Izu LT, Cheng H, Kuschel M et al. 2000. Gi-dependent localization of β2-adrenergic receptor signaling to L-type Ca2+ channels. Biophys. J. 79:2547–56
    [Google Scholar]
  59. 59. 
    Qian H, Matt L, Zhang M, Nguyen M, Patriarchi T et al. 2012. β2-Adrenergic receptor supports prolonged theta tetanus–induced LTP. J. Neurophysiol. 107:2703–12
    [Google Scholar]
  60. 60. 
    Zamponi GW, Striessnig J, Koschak A, Dolphin AC 2015. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol. Rev. 67:821–70
    [Google Scholar]
  61. 61. 
    Striessnig J. 2008. Ca2+ channel blockers. Encyclopedia of Molecular Pharmacology S Offermanns, W Rosenthal 295–300 Berlin: Springer-Verlag
    [Google Scholar]
  62. 62. 
    Steinberg SF. 1999. The molecular basis for distinct β-adrenergic receptor subtype actions in cardiomyocytes. Circ. Res. 85:1101–11
    [Google Scholar]
  63. 63. 
    Kamp TJ, Hell JW. 2000. Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C. Circ. Res. 87:1095–102
    [Google Scholar]
  64. 64. 
    Tykocki NR, Boerman EM, Jackson WF 2017. Smooth muscle ion channels and regulation of vascular tone in resistance arteries and arterioles. Compr. Physiol. 7:485–581
    [Google Scholar]
  65. 65. 
    Navedo MF, Nieves-Cintron M, Amberg GC, Yuan C, Votaw VS et al. 2008. AKAP150 is required for stuttering persistent Ca2+ sparklets and angiotensin II-induced hypertension. Circ. Res. 102:e20–35
    [Google Scholar]
  66. 66. 
    Nystoriak MA, Nieves-Cintron M, Nygren PJ, Hinke SA, Nichols CB et al. 2014. AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus. Circ. Res. 214:607–15
    [Google Scholar]
  67. 67. 
    Mercado J, Baylie R, Navedo MF, Yuan C, Scott JD et al. 2014. Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle. J. Gen. Physiol. 143:559–75
    [Google Scholar]
  68. 68. 
    Navedo MF, Amberg GC. 2013. Local regulation of L-type Ca2+ channel sparklets in arterial smooth muscle. Microcirculation 20:290–98
    [Google Scholar]
  69. 69. 
    Navedo MF, Takeda Y, Nieves-Cintron M, Molkentin JD, Santana LF 2010. Elevated Ca2+ sparklet activity during acute hyperglycemia and diabetes in cerebral arterial smooth muscle cells. Am. J. Physiol. Cell Physiol. 298:C211–20
    [Google Scholar]
  70. 70. 
    Prada MP, Syed AU, Buonarati OR, Reddy GR, Nystoriak MA et al. 2019. A GS-coupled purinergic receptor boosts Ca2+ influx and vascular contractility during diabetic hyperglycemia. eLife 8:e42214
    [Google Scholar]
  71. 71. 
    Nieves-Cintron M, Amberg GC, Nichols CB, Molkentin JD, Santana LF 2007. Activation of NFATc3 down-regulates the β1 subunit of large conductance, calcium-activated K+ channels in arterial smooth muscle and contributes to hypertension. J. Biol. Chem. 282:3231–40
    [Google Scholar]
  72. 72. 
    Nieves-Cintron M, Syed AU, Nystoriak MA, Navedo MF 2018. Regulation of voltage-gated potassium channels in vascular smooth muscle during hypertension and metabolic disorders. Microcirculation 25:e12423
    [Google Scholar]
  73. 73. 
    Tajada S, Moreno CM, O'Dwyer S, Woods S, Sato D et al. 2017. Distance constraints on activation of TRPV4 channels by AKAP150-bound PKCα in arterial myocytes. J. Gen. Physiol. 149:639–59
    [Google Scholar]
  74. 74. 
    Moore CL, Nelson PL, Parelkar NK, Rusch NJ, Rhee SW 2014. Protein kinase A-phosphorylated KV1 channels in PSD95 signaling complex contribute to the resting membrane potential and diameter of cerebral arteries. Circ. Res. 114:1258–67
    [Google Scholar]
  75. 75. 
    Moore CL, McClenahan SJ, Hanvey HM, Jang DS, Nelson PL et al. 2015. β1-Adrenergic receptor-mediated dilation of rat cerebral artery requires Shaker-type KV1 channels on PSD95 scaffold. J. Cereb. Blood Flow Metab. 35:1537–46
    [Google Scholar]
  76. 76. 
    Colledge M, Dean RA, Scott GK, Langeberg LK, Huganir RL, Scott JD 2000. Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex. Neuron 27:107–19
    [Google Scholar]
  77. 77. 
    Chen CY, Matt L, Hell JW, Rogawski MA 2014. Perampanel inhibition of AMPA receptor currents in cultured hippocampal neurons. PLOS ONE 9:e108021
    [Google Scholar]
  78. 78. 
    Grooms SY, Opitz T, Bennett MV, Zukin RS 2000. Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. PNAS 97:3631–36
    [Google Scholar]
  79. 79. 
    Liu SJ, Zukin RS. 2007. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci 30:126–34
    [Google Scholar]
  80. 80. 
    Spaethling JM, Klein DM, Singh P, Meaney DF 2008. Calcium-permeable AMPA receptors appear in cortical neurons after traumatic mechanical injury and contribute to neuronal fate. J. Neurotrauma 25:1207–16
    [Google Scholar]
  81. 81. 
    Henley JM, Wilkinson KA. 2016. Synaptic AMPA receptor composition in development, plasticity and disease. Nat. Rev. Neurosci. 17:337–50
    [Google Scholar]
  82. 82. 
    Walsh DM, Selkoe DJ. 2007. Aβ oligomers—a decade of discovery. J. Neurochem. 101:1172–84
    [Google Scholar]
  83. 83. 
    Hampel H, Prvulovic D, Teipel S, Jessen F, Luckhaus C et al. 2011. The future of Alzheimer's disease: the next 10 years. Prog. Neurobiol. 95:718–28
    [Google Scholar]
  84. 84. 
    Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE et al. 2008. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14:837–42
    [Google Scholar]
  85. 85. 
    Zhao WQ, Santini F, Breese R, Ross D, Zhang XD et al. 2010. Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption. J. Biol. Chem. 285:7619–32
    [Google Scholar]
  86. 86. 
    Zhang H, Etherington LA, Hafner AS, Belelli D, Coussen F et al. 2013. Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule. Mol. Psychiatry 18:471–84
    [Google Scholar]
  87. 87. 
    Schnell E, Sizemore M, Karimzadegan S, Chen L, Bredt DS, Nicoll RA 2002. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. PNAS 99:13902–7
    [Google Scholar]
  88. 88. 
    Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW 1998. SAP97 is associated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J. Biol. Chem. 273:19518–24
    [Google Scholar]
  89. 89. 
    Tavalin SJ, Colledge M, Hell JW, Langeberg LK, Huganir RL, Scott JD 2002. Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares properties with long-term depression. J. Neurosci. 22:3044–51
    [Google Scholar]
  90. 90. 
    Zhang M, Patriarchi T, Stein IS, Qian H, Matt L et al. 2013. Adenylyl cyclase anchoring by a kinase anchor protein AKAP5 (AKAP79/150) is important for postsynaptic β-adrenergic signaling. J. Biol. Chem. 288:17918–31
    [Google Scholar]
  91. 91. 
    Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF 2000. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J. Neurosci. 20:89–102
    [Google Scholar]
  92. 92. 
    Guidotti G, Brambilla L, Rossi D 2017. Cell-penetrating peptides: from basic research to clinics. Trends Pharmacol. Sci. 38:406–24
    [Google Scholar]
  93. 93. 
    Kauffman WB, Fuselier T, He J, Wimley WC 2015. Mechanism matters: a taxonomy of cell penetrating peptides. Trends Biochem. Sci. 40:749–64
    [Google Scholar]
  94. 94. 
    Schwarze SR, Dowdy SF. 2000. In vivo protein transduction: intracellular delivery of biologically active proteins, compounds and DNA. Trends Pharmacol. Sci. 21:45–48
    [Google Scholar]
  95. 95. 
    Frankel AD, Pabo CO. 1988. Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55:1189–93
    [Google Scholar]
  96. 96. 
    Green M, Loewenstein PM. 1988. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 55:1179–88
    [Google Scholar]
  97. 97. 
    Joliot A, Pernelle C, Deagostini-Bazin H, Prochiantz A 1991. Antennapedia homeobox peptide regulates neural morphogenesis. PNAS 88:1864–68
    [Google Scholar]
  98. 98. 
    Derossi D, Joliot AH, Chassaing G, Prochiantz A 1994. The third helix of the Antennapedia homeodomain translocates through biological membranes. J. Biol. Chem. 269:10444–50
    [Google Scholar]
  99. 99. 
    Park J, Ryu J, Kim KA, Lee HJ, Bahn JH et al. 2002. Mutational analysis of a human immunodeficiency virus type 1 Tat protein transduction domain which is required for delivery of an exogenous protein into mammalian cells. J. Gen. Virol. 83:1173–81
    [Google Scholar]
  100. 100. 
    Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF 1999. In vivo protein transduction: delivery of a biological active protein into the mouse. Science 285:1569–72
    [Google Scholar]
  101. 101. 
    Passafaro M, Sala C, Niethammer M, Sheng M 1999. Microtubule binding by CRIPT and its potential role in the synaptic clustering of PSD-95. Nat. Neurosci. 2:1063–69
    [Google Scholar]
  102. 102. 
    Sanhueza M, Fernandez-Villalobos G, Stein IS, Kasumova G, Zhang P et al. 2011. Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. J. Neurosci. 31:9170–78
    [Google Scholar]
  103. 103. 
    Aarts M, Liu Y, Liu L, Besshoh S, Arundine M et al. 2002. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 298:846–50
    [Google Scholar]
  104. 104. 
    Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG et al. 1998. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nat. Med. 4:1449–52
    [Google Scholar]
  105. 105. 
    Schwartz MA, Schaller MD, Ginsberg MH 1995. Integrins: emerging paradigms of signal transduction. Ann. Rev. Cell Dev. Biol. 11:549–99
    [Google Scholar]
  106. 106. 
    Brittain JM, Duarte DB, Wilson SM, Zhu W, Ballard C et al. 2011. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex. Nat. Med. 17:822–29
    [Google Scholar]
  107. 107. 
    Lu Y, Allen M, Halt AR, Weisenhaus M, Dallapiazza RF et al. 2007. Age-dependent requirement of AKAP150-anchored PKA and GluR2-lacking AMPA receptors in LTP. EMBO J 26:4879–90
    [Google Scholar]
  108. 108. 
    Matsushita M, Tomizawa K, Moriwaki A, Li ST, Terada H, Matsui H 2001. A high-efficiency protein transduction system demonstrating the role of PKA in long-lasting long-term potentiation. J. Neurosci. 21:6000–7
    [Google Scholar]
  109. 109. 
    Nelson AR, Borland L, Allbritton NL, Sims CE 2007. Myristoyl-based transport of peptides into living cells. Biochemistry 46:14771–81
    [Google Scholar]
  110. 110. 
    Francois-Moutal L, Wang Y, Moutal A, Cottier KE, Melemedjian OK et al. 2015. A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors. Pain 156:1247–64
    [Google Scholar]
  111. 111. 
    Wootten D, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM 2018. Mechanisms of signalling and biased agonism in G protein–coupled receptors. Nat. Rev. Mol. Cell Biol. 19:638–53
    [Google Scholar]
  112. 112. 
    Dupre DJ, Robitaille M, Rebois RV, Hebert TE 2009. The role of Gβγ subunits in the organization, assembly, and function of GPCR signaling complexes. Annu. Rev. Pharmacol. Toxicol. 49:31–56
    [Google Scholar]
  113. 113. 
    Lefkowitz RJ. 2013. Arrestins come of age: a personal historical perspective. Prog. Mol. Biol. Transl. Sci. 118:3–18
    [Google Scholar]
  114. 114. 
    Smith JS, Rajagopal S. 2016. The β-arrestins: multifunctional regulators of G protein–coupled receptors. J. Biol. Chem. 291:8969–77
    [Google Scholar]
  115. 115. 
    Lodowski DT, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJ 2003. Keeping G proteins at bay: a complex between G protein–coupled receptor kinase 2 and Gβγ. Science 300:1256–62
    [Google Scholar]
  116. 116. 
    Bouvier M, Hausdorff WP, De Blasi A, O'Dowd BF, Kobilka BK et al. 1988. Removal of phosphorylation sites from the β2-adrenergic receptor delays onset of agonist-promoted desensitization. Nature 333:370–73
    [Google Scholar]
  117. 117. 
    Hausdorff WP, Caron MG, Lefkowitz RJ 1990. Turning off the signal: desensitization of β-adrenergic receptor function. Faseb J 4:2881–89
    [Google Scholar]
  118. 118. 
    Shi Q, Li M, Mika D, Fu Q, Kim S et al. 2017. Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes. Cardiovasc. Res. 113:656–70
    [Google Scholar]
  119. 119. 
    Toth AD, Prokop S, Gyombolai P, Varnai P, Balla A et al. 2018. Heterologous phosphorylation-induced formation of a stability lock permits regulation of inactive receptors by β-arrestins. J. Biol. Chem. 293:876–92
    [Google Scholar]
  120. 120. 
    DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK 2007. β-Arrestins and cell signaling. Annu. Rev. Physiol. 69:483–510
    [Google Scholar]
  121. 121. 
    Patel PA, Tilley DG, Rockman HA 2008. β-Arrestin-mediated signaling in the heart. Circ. J. 72:1725–29
    [Google Scholar]
  122. 122. 
    Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S et al. 1999. β-Arrestin-dependent formation of β2 adrenergic receptor–Src protein kinase complexes. Science 283:655–61
    [Google Scholar]
  123. 123. 
    Noma T, Lemaire A, Naga Prasad SV, Barki-Harrington L, Tilley DG et al. 2007. β-Arrestin-mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J. Clin. Investig. 117:2445–58
    [Google Scholar]
  124. 124. 
    Kook S, Zhan X, Kaoud TS, Dalby KN, Gurevich VV, Gurevich EV 2013. Arrestin-3 binds c-Jun N-terminal kinase 1 (JNK1) and JNK2 and facilitates the activation of these ubiquitous JNK isoforms in cells via scaffolding. J. Biol. Chem. 288:37332–42
    [Google Scholar]
  125. 125. 
    Hilger D, Masureel M, Kobilka BK 2018. Structure and dynamics of GPCR signaling complexes. Nat. Struct. Mol. Biol. 25:4–12
    [Google Scholar]
  126. 126. 
    Furness SGB, Liang YL, Nowell CJ, Halls ML, Wookey PJ et al. 2016. Ligand-dependent modulation of G protein conformation alters drug efficacy. Cell 167:739–49.e11
    [Google Scholar]
  127. 127. 
    Gregorio GG, Masureel M, Hilger D, Terry DS, Juette M et al. 2017. Single-molecule analysis of ligand efficacy in β2AR-G-protein activation. Nature 547:68–73
    [Google Scholar]
  128. 128. 
    Lee M-H, Appleton KM, Strungs EG, Kwon JY, Morinelli TA et al. 2016. The conformational signature of β-arrestin2 predicts its trafficking and signalling functions. Nature 531:665–68
    [Google Scholar]
  129. 129. 
    Liang YL, Khoshouei M, Glukhova A, Furness SGB, Zhao P et al. 2018. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555:121–25
    [Google Scholar]
  130. 130. 
    Nuber S, Zabel U, Lorenz K, Nuber A, Milligan G et al. 2016. β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle. Nature 531:661–64
    [Google Scholar]
  131. 131. 
    Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CM et al. 2011. Distinct phosphorylation sites on the β2-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin. Sci. Signal. 4:ra51
    [Google Scholar]
  132. 132. 
    Butcher AJ, Prihandoko R, Kong KC, McWilliams P, Edwards JM et al. 2011. Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code. J. Biol. Chem. 286:11506–18
    [Google Scholar]
  133. 133. 
    Carr R, Du Y, Quoyer J, Panettieri RA Jr., Janz JM et al. 2014. Development and characterization of pepducins as Gs-biased allosteric agonists. J. Biol. Chem. 289:35668–84
    [Google Scholar]
  134. 134. 
    Carr R, Schilling J, Song J, Carter RL, Du Y et al. 2016. β-Arrestin-biased signaling through the β2-adrenergic receptor promotes cardiomyocyte contraction. PNAS 113:E4107–16
    [Google Scholar]
  135. 135. 
    Vincke C, Muyldermans S. 2012. Introduction to heavy chain antibodies and derived nanobodies. Methods Mol. Biol. 911:15–26
    [Google Scholar]
  136. 136. 
    Staus DP, Wingler LM, Strachan RT, Rasmussen SG, Pardon E et al. 2014. Regulation of β2-adrenergic receptor function by conformationally selective single-domain intrabodies. Mol. Pharmacol. 85:472–81
    [Google Scholar]
  137. 137. 
    Ghosh E, Srivastava A, Baidya M, Kumari P, Dwivedi H et al. 2017. A synthetic intrabody-based selective and generic inhibitor of GPCR endocytosis. Nat. Nanotechnol. 12:1190–98
    [Google Scholar]
  138. 138. 
    Daniels DA, Sohal AK, Rees S, Grisshammer R 2002. Generation of RNA aptamers to the G-protein-coupled receptor for neurotensin, NTS-1. Anal. Biochem. 305:214–26
    [Google Scholar]
  139. 139. 
    Tuerk C, Gold L. 1990. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505–10
    [Google Scholar]
  140. 140. 
    Ni S, Yao H, Wang L, Lu J, Jiang F et al. 2017. Chemical modifications of nucleic acid aptamers for therapeutic purposes. Int. J. Mol. Sci. 18:1683
    [Google Scholar]
  141. 141. 
    Youn P, Chen Y, Furgeson DY 2014. A myristoylated cell-penetrating peptide bearing a transferrin receptor-targeting sequence for neuro-targeted siRNA delivery. Mol. Pharm. 11:486–95
    [Google Scholar]
  142. 142. 
    Kahsai AW, Wisler JW, Lee J, Ahn S, Cahill TJ et al. 2016. Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor. Nat. Chem. Biol. 12:709–16
    [Google Scholar]
  143. 143. 
    Bohm M, Eschenhagen T, Gierschik P, Larisch K, Lensche H et al. 1994. Radioimmunochemical quantification of Giα in right and left ventricles from patients with ischaemic and dilated cardiomyopathy and predominant left ventricular failure. J. Mol. Cell Cardiol. 26:133–49
    [Google Scholar]
  144. 144. 
    Feldman AM, Cates AE, Veazey WB, Hershberger RE, Bristow MR et al. 1988. Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J. Clin. Investig. 82:189–97
    [Google Scholar]
  145. 145. 
    Zhu WZ, Zheng M, Koch WJ, Lefkowitz RJ, Kobilka BK, Xiao RP 2001. Dual modulation of cell survival and cell death by β2-adrenergic signaling in adult mouse cardiac myocytes. PNAS 98:1607–12
    [Google Scholar]
  146. 146. 
    Oliveria SF, Gomez LL, Dell'Acqua ML 2003. Imaging kinase–AKAP79–phosphatase scaffold complexes at the plasma membrane in living cells using FRET microscopy. J. Cell Biol. 160:101–12
    [Google Scholar]
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