Abstract
The concept of G protein-coupled receptors initially arose from studies of the β-adrenoceptor, adenylyl cyclase, and cAMP signalling pathway. Since then both canonical G protein-coupled receptor signalling pathways and emerging paradigms in receptor signalling have been defined by experiments focused on adrenoceptors. Here, we discuss the evidence for G protein coupling specificity of the nine adrenoceptor subtypes. We summarise the ability of each of the adrenoceptors to activate proximal signalling mediators including cAMP, calcium, mitogen-activated protein kinases, and protein kinase C pathways. Finally, we highlight the importance of precise spatial and temporal control of adrenoceptor signalling that is controlled by the localisation of receptors at intracellular membranes and in larger protein complexes.
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References
Agarwal SR, Sherpa RT, Moshal KS, Harvey RD (2022) Compartmentalized cAMP signaling in cardiac ventricular myocytes. Cell Signal 89:110172. https://doi.org/10.1016/j.cellsig.2021.110172
Akhter SA, Milano CA, Shotwell KF, Cho M-C, Rockman HA, Lefkowitz RJ, Koch WJ (1997) Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors: in vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling. J Biol Chem 272:21253–21259. https://doi.org/10.1074/jbc.272.34.21253
Akinaga J, García-Sáinz JA, Pupo AS (2019) Updates in the function and regulation of α1-adrenoceptors. Br J Pharmacol 176:2343–2357. https://doi.org/10.1111/bph.14617
Altosaar K, Balaji P, Bond RA, Bylund DB, Cotecchia S, Devost D, Doze VA, Eikenburg DC, Gora S, Goupil E, Graham RM, Hébert T, Hieble JP, Hills R, Kan S, Machkalyan G, Michel MC, Minneman KP, Parra S, Perez D, Sleno R, Summers RJ, Zylbergold P (2019) Adrenoceptors (version 2019.3) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide Pharmacol CITE. https://doi.org/10.2218/gtopdb/F4/2021.3
Amatruda TT, Steele DA, Slepak VZ, Simon MI (1991) G alpha 16, a G protein alpha subunit specifically expressed in hematopoietic cells. Proc Natl Acad Sci U S A 88:5587–5591. https://doi.org/10.1073/pnas.88.13.5587
Appert-Collin A, Cotecchia S, Nenniger-Tosato M, Pedrazzini T, Diviani D (2007) The A-kinase anchoring protein (AKAP)-Lbc-signaling complex mediates alpha1 adrenergic receptor-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 104:10140–10145. https://doi.org/10.1073/pnas.0701099104
Arch JR, Kaumann AJ (1993) Beta 3 and atypical beta-adrenoceptors. Med Res Rev 13:663–729. https://doi.org/10.1002/med.2610130604
Armaiz-Pena GN, Allen JK, Cruz A, Stone RL, Nick AM, Lin YG, Han LY, Mangala LS, Villares GJ, Vivas-Mejia P, Rodriguez-Aguayo C, Nagaraja AS, Gharpure KM, Wu Z, English RD, Soman KV, Shahzad MMK, Zigler M, Deavers MT, Zien A, Soldatos TG, Jackson DB, Wiktorowicz JE, Torres-Lugo M, Young T, De Geest K, Gallick GE, Bar-Eli M, Lopez-Berestein G, Cole SW, Lopez GE, Lutgendorf SK, Sood AK (2013) Src activation by β-adrenoreceptors is a key switch for tumour metastasis. Nat Commun 4:1403. https://doi.org/10.1038/ncomms2413
Avet C, Mancini A, Breton B, Le Gouill C, Hauser AS, Normand C, Kobayashi H, Gross F, Hogue M, Lukasheva V, St-Onge S, Carrier M, Héroux M, Morissette S, Fauman EB, Fortin JP, Schann S, Leroy X, Gloriam DE, Bouvier M (2022) Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs. Elife 11:e74101. https://doi.org/10.7554/eLife.74101
Baek M, DiMaio F, Anishchenko I, Dauparas J, Ovchinnikov S, Lee GR, Wang J, Cong Q, Kinch LN, Schaeffer RD, Millán C, Park H, Adams C, Glassman CR, DeGiovanni A, Pereira JH, Rodrigues AV, van Dijk AA, Ebrecht AC, Opperman DJ, Sagmeister T, Buhlheller C, Pavkov-Keller T, Rathinaswamy MK, Dalwadi U, Yip CK, Burke JE, Garcia KC, Grishin NV, Adams PD, Read RJ, Baker D (2021) Accurate prediction of protein structures and interactions using a three-track neural network. Science 373:871–876. https://doi.org/10.1126/science.abj8754
Bastug-Ozel Z, Wright PT, Kraft AE, Pavlovic D, Howie J, Froese A, Fuller W, Gorelik J, Shattock MJ, Nikolaev VO (2019) Heart failure leads to altered beta2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,K ATPase microdomain. Cardiovasc Res 115:546–555. https://doi.org/10.1093/cvr/cvy221
Bathe-Peters M, Gmach P, Boltz H-H, Einsiedel J, Gotthardt M, Hübner H, Gmeiner P, Lohse MJ, Annibale P (2021) Visualization of beta-adrenergic receptor dynamics and differential localization in cardiomyocytes. Proc Natl Acad Sci U S A 118:e2101119118. https://doi.org/10.1073/pnas.2101119118
Beavo JA, Brunton LL (2002) Cyclic nucleotide research -- still expanding after half a century. Nat Rev Mol Cell Biol 3:710–718. https://doi.org/10.1038/nrm911
Belevych AE, Juranek I, Harvey RD (2004) Protein kinase C regulates functional coupling of β1-adrenergic receptors to Gi/o-mediated responses in cardiac myocytes. FASEB J 18:1–19. https://doi.org/10.1096/fj.03-0647fje
Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205. https://doi.org/10.1038/415198a
Bos JL (1998) All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral. EMBO J 17:6776–6782. https://doi.org/10.1093/emboj/17.23.6776
Bowman SL, Shiwarski DJ, Puthenveedu MA (2016) Distinct G protein-coupled receptor recycling pathways allow spatial control of downstream G protein signaling. J Cell Biol 214:797–806. https://doi.org/10.1083/jcb.201512068
Braun C, Parks XX, Qudsi H, Lopes CM (2020) PKCbeta-II specifically regulates KCNQ1/KCNE1 channel membrane localization. J Mol Cell Cardiol 138:283–290. https://doi.org/10.1016/j.yjmcc.2019.10.010
Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S (1986) Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res 59:297–309. https://doi.org/10.1161/01.RES.59.3.297
Brodde OE (1991) Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev 43:203–242
Bruzzone A, Saulière A, Finana F, Sénard J-M, Lüthy I, Galés C (2014) Dosage-dependent regulation of cell proliferation and adhesion through dual β2-adrenergic receptor/cAMP signals. FASEB J 28:1342–1354. https://doi.org/10.1096/fj.13-239285
Buchwalow IB, Kopiov OV, Schulze W (1981) Ultracytochemical localization of adenylate cyclase activity in rat thymocytes. Histochemistry 72:625–634. https://doi.org/10.1007/bf00493279
Bünemann M, Bücheler MM, Philipp M, Lohse MJ, Hein L (2001) Activation and deactivation kinetics of alpha 2A- and alpha 2C-adrenergic receptor-activated G protein-activated inwardly rectifying K+ channel currents. J Biol Chem 276:47512–47517. https://doi.org/10.1074/jbc.M108652200
Bylund DB (1988) Subtypes of alpha 2-adrenoceptors: pharmacological and molecular biological evidence converge. Trends Pharmacol Sci 9:356–361. https://doi.org/10.1016/0165-6147(88)90254-4
Calabrese EJ, Giordano J (2021) Ultra low doses and biological amplification: approaching Avogadro's number. Pharmacol Res 170:105738. https://doi.org/10.1016/j.phrs.2021.105738
Calebiro D, Grimes J (2020) G protein-coupled receptor pharmacology at the single-molecule level. Annu Rev Pharmacol Toxicol 60:73–87. https://doi.org/10.1146/annurev-pharmtox-010919-023348
Cariolato L, Cavin S, Diviani D (2011) A-kinase anchoring protein (AKAP)-Lbc anchors a PKN-based signaling complex involved in α1-adrenergic receptor-induced p38 activation. J Biol Chem 286:7925–7937. https://doi.org/10.1074/jbc.M110.185645
Chaudhry A, MacKenzie RG, Georgic LM, Granneman JG (1994) Differential interaction of beta 1- and beta 3-adrenergic receptors with Gi in rat adipocytes. Cell Signal 6:457–465. https://doi.org/10.1016/0898-6568(94)90093-0
Chen L, El-Sherif N, Boutjdir M (1996) Alpha1-adrenergic activation inhibits beta-adrenergic stimulated unitary Ca2+ currents in cardiac ventricular myocytes. Circ Res 79:184–193. https://doi.org/10.1161/01.RES.79.2.184
Cheng H, Farquhar MG (1976a) Presence of adenylate cyclase activity in Golgi and other fractions from rat liver. I Biochemical determination. J Cell Biol 70:660–670. https://doi.org/10.1083/jcb.70.3.660
Cheng H, Farquhar MG (1976b) Presence of adenylate cyclase activity in Golgi and other fractions from rat liver. II. Cytochemical localization within Golgi and ER membranes. J Cell Biol 70:671–684. https://doi.org/10.1083/jcb.70.3.671
Civciristov S, Ellisdon AM, Suderman R, Pon CK, Evans BA, Kleifeld O, Charlton SJ, Hlavacek WS, Canals M, Halls ML (2018) Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations. Sci Signal 11:eaan1188. https://doi.org/10.1126/scisignal.aan1188
Civciristov S, Halls ML (2019) Signalling in response to sub-picomolar concentrations of active compounds: pushing the boundaries of GPCR sensitivity. Br J Pharmacol 176:2382–2401. https://doi.org/10.1111/bph.14636
Copik AJ, Baldys A, Nguyen K, Sahdeo S, Ho H, Kosaka A, Dietrich PJ, Fitch B, Raymond JR, Ford APDW, Button D, Milla ME (2015) Isoproterenol acts as a biased agonist of the alpha-1A-adrenoceptor that selectively activates the MAPK/ERK pathway. PloS One 10:e0115701. https://doi.org/10.1371/journal.pone.0115701
Cotecchia S (2010) The α1-adrenergic receptors: diversity of signaling networks and regulation. J Recept Signal Transduct Res 30:410–419. https://doi.org/10.3109/10799893.2010.518152
Cotecchia S, Kobilka BK, Daniel KW, Nolan RD, Lapetina EY, Caron MG, Lefkowitz RJ, Regan JW (1990) Multiple second messenger pathways of alpha-adrenergic receptor subtypes expressed in eukaryotic cells. J Biol Chem 265:63–69
Crilly SE, Puthenveedu MA (2021) Compartmentalized GPCR signaling from intracellular membranes. J Membr Biol 254:259–271. https://doi.org/10.1007/s00232-020-00158-7
Daaka Y, Luttrell LM, Lefkowitz RJ (1997) Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 390:88–91. https://doi.org/10.1038/36362
Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberg RJ, Horne MC, Hoshi T, Hell JW (2001) A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2. Science 293:98–101. https://doi.org/10.1126/science.293.5527.98
Davel AP, Brum PC, Rossoni LV (2014) Isoproterenol induces vascular oxidative stress and endothelial dysfunction via a Giα-coupled β2-adrenoceptor signaling pathway. PloS One 9:e91877. https://doi.org/10.1371/journal.pone.0091877
DeFea KA (2011) Beta-arrestins as regulators of signal termination and transduction: how do they determine what to scaffold? Cell Signal 23:621–629. https://doi.org/10.1016/j.cellsig.2010.10.004
DeGraff JL, Gagnon AW, Benovic JL, Orsini MJ (1999) Role of arrestins in endocytosis and signaling of alpha2-adrenergic receptor subtypes. J Biol Chem 274:11253–11259. https://doi.org/10.1074/jbc.274.16.11253
Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E, Diehl RE, Mumford RA, Slater EE, Sigal IS, Caron MG, Lefkowitz RJ, Strader CD (1986) Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321:75–79. https://doi.org/10.1038/321075a0
Dorn GW 2nd, Oswald KJ, McCluskey TS, Kuhel DG, Liggett SB (1997) Alpha 2A-adrenergic receptor stimulated calcium release is transduced by Gi-associated G(beta gamma)-mediated activation of phospholipase C. Biochemistry 36:6415–6423. https://doi.org/10.1021/bi970080s
Drinnan SL, Hope BT, Snutch TP, Vincent SR (1991) G(olf) in the basal ganglia. Mol Cell Neurosci 2:66–70. https://doi.org/10.1016/1044-7431(91)90040-u
Dumaz N, Marais R (2003) Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. J Biol Chem 278:29819–29823. https://doi.org/10.1074/jbc.C300182200
Dumaz N, Marais R (2005) Integrating signals between cAMP and the RAS/RAF/MEK/ERK signalling pathways. Based on the anniversary prize of the Gesellschaft fur Biochemie und Molekularbiologie lecture delivered on 5 July 2003 at the special FEBS meeting in Brussels. FEBS J 272:3491–3504. https://doi.org/10.1111/j.1742-4658.2005.04763.x
Eason MG, Kurose H, Holt BD, Raymond JR, Liggett SB (1992) Simultaneous coupling of alpha 2-adrenergic receptors to two G-proteins with opposing effects. Subtype-selective coupling of alpha 2C10, alpha 2C4, and alpha 2C2 adrenergic receptors to Gi and Gs. J Biol Chem 267:15795–15801
Eblen ST (2018) Chapter four - extracellular-regulated kinases: signaling from Ras to ERK substrates to control biological outcomes. In: Tew KD, Fisher PB (eds) Advances in cancer research, vol 138. Academic Press, pp 99–142
Eichel K, Jullié D, Barsi-Rhyne B, Latorraca NR, Masureel M, Sibarita J-B, Dror RO, von Zastrow M (2018) Catalytic activation of β-arrestin by GPCRs. Nature 557:381–386. https://doi.org/10.1038/s41586-018-0079-1
Eichel K, von Zastrow M (2018) Subcellular organization of GPCR signaling. Trends Pharmacol Sci 39:200–208. https://doi.org/10.1016/j.tips.2017.11.009
Ellisdon AM, Halls ML (2016) Compartmentalization of GPCR signalling controls unique cellular responses. Biochem Soc Trans 44:562–567. https://doi.org/10.1042/BST20150236
Endoh M (2016) Cardiac α1-adrenoceptors and inotropy: myofilament Ca2+ sensitivity, intracellular Ca2+ mobilization, signaling pathway, and pathophysiological relevance. Circ Res 119:587–590. https://doi.org/10.1161/circresaha.116.309502
Enserink JM, Christensen AE, de Rooij J, van Triest M, Schwede F, Genieser HG, Døskeland SO, Blank JL, Bos JL (2002) A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nat Cell Biol 4:901–906. https://doi.org/10.1038/ncb874
Ferguson SS (2001) Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 53:1–24
Fink EA et al (2022) Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor. Science 377:eabn7065. https://doi.org/10.1126/science.abn7065
Friedman J, Babu B, Clark RB (2002) β2-adrenergic receptor lacking the cyclic AMP-dependent protein kinase consensus sites fully activates extracellular signal-regulated kinase 1/2 in human embryonic kidney 293 cells: lack of evidence for Gs/Gi switching. Mol Pharmacol 62:1094–1102. https://doi.org/10.1124/mol.62.5.1094
García-Sáinz JA, Vázquez-Prado J, del Carmen ML (2000) Alpha 1-adrenoceptors: function and phosphorylation. Eur J Pharmacol 389:1–12. https://doi.org/10.1016/s0014-2999(99)00896-1
Gilman AG (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56:615–649. https://doi.org/10.1146/annurev.bi.56.070187.003151
Gollasch M, Hescheler J, Spicher K, Klinz FJ, Schultz G, Rosenthal W (1991) Inhibition of Ca2+ channels via alpha 2-adrenergic and muscarinic receptors in pheochromocytoma (PC-12) cells. Am J Physiol 260:C1282–C1289. https://doi.org/10.1152/ajpcell.1991.260.6.C1282
Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59:675–680. https://doi.org/10.1016/0092-8674(89)90013-5
Grundmann M, Merten N, Malfacini D, Inoue A, Preis P, Simon K, Rüttiger N, Ziegler N, Benkel T, Schmitt NK, Ishida S, Müller I, Reher R, Kawakami K, Inoue A, Rick U, Kühl T, Imhof D, Aoki J, König GM, Hoffmann C, Gomeza J, Wess J, Kostenis E (2018) Lack of beta-arrestin signaling in the absence of active G proteins. Nat Commun 9:341. https://doi.org/10.1038/s41467-017-02661-3
Guimond J, Mamarbachi AM, Allen BG, Rindt H, Hébert TE (2005) Role of specific protein kinase C isoforms in modulation of β1- and β2-adrenergic receptors. Cell Signal 17:49–58. https://doi.org/10.1016/j.cellsig.2004.05.012
Gutkind JS, Kostenis E (2018) Arrestins as rheostats of GPCR signalling. Nat Rev Mol Cell Biol 19:615–616. https://doi.org/10.1038/s41580-018-0041-y
Halls ML (2019) Localised GPCR signalling as revealed by FRET biosensors. Curr Opin Cell Biol 57:48–56. https://doi.org/10.1016/j.ceb.2018.11.001
Halls ML, Canals M (2018) Genetically encoded FRET biosensors to illuminate compartmentalised GPCR signalling. Trends Pharmacol Sci 39:148–157. https://doi.org/10.1016/j.tips.2017.09.005
Halls ML, Cooper DM (2011) Regulation by Ca2+-signaling pathways of adenylyl cyclases. Cold Spring Harb Perspect Biol 3:a004143. https://doi.org/10.1101/cshperspect.a004143
Hamed O, Joshi R, Michi AN, Kooi C, Giembycz MA (2021) β2-adrenoceptor agonists promote extracellular signal-regulated kinase 1/2 dephosphorylation in human airway epithelial cells by canonical, cAMP-driven signaling independently of β-arrestin 2. Mol Pharmacol 100:388–405. https://doi.org/10.1124/molpharm.121.000294
Hanoune J, Defer N (2001) Regulation and role of adenylyl cyclase isoforms. Annu Rev Pharmacol Toxicol 41:145–174. https://doi.org/10.1146/annurev.pharmtox.41.1.145
Hausdorff WP, Bouvier M, O'Dowd BF, Irons GP, Caron MG, Lefkowitz RJ (1989) Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization. J Biol Chem 264:12657–12665
Hill SJ (2006) G-protein-coupled receptors: past, present and future. Br J Pharmacol 147(Suppl 1):S27–S37. https://doi.org/10.1038/sj.bjp.0706455
Holmberg CI, Kukkonen JP, Bischoff A, Näsman J, Courtney MJ, Michel MC, Akerman KE (1998) Alpha2B-adrenoceptors couple to Ca2+ increase in both endogenous and recombinant expression systems. Eur J Pharmacol 363:65–74. https://doi.org/10.1016/s0014-2999(98)00780-8
Huang Y, Wright CD, Merkwan CL, Baye NL, Liang Q, Simpson PC, O'Connell TD (2007) An alpha1A-adrenergic-extracellular signal-regulated kinase survival signaling pathway in cardiac myocytes. Circulation 115:763–772. https://doi.org/10.1161/circulationaha.106.664862
Hucho TB, Dina OA, Levine JD (2005) Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. J Neurosci 25:6119–6126. https://doi.org/10.1523/jneurosci.0285-05.2005
Inoue A, Raimondi F, Kadji FMN, Singh G, Kishi T, Uwamizu A, Ono Y, Shinjo Y, Ishida S, Arang N, Kawakami K, Gutkind JS, Aoki J, Russell RB (2019) Illuminating G-protein-coupling selectivity of GPCRs. Cell 177:1933–1947.e1925. https://doi.org/10.1016/j.cell.2019.04.044
Insel PA, Murray F, Yokoyama U, Romano S, Yun H, Brown L, Snead A, Lu D, Aroonsakool N (2012) cAMP and Epac in the regulation of tissue fibrosis. Br J Pharmacol 166:447–456. https://doi.org/10.1111/j.1476-5381.2012.01847.x
Irannejad R, Pessino V, Mika D, Huang B, Wedegaertner PB, Conti M, von Zastrow M (2017) Functional selectivity of GPCR-directed drug action through location bias. Nat Chem Biol 13:799–806. https://doi.org/10.1038/nchembio.2389
Irannejad R, Tomshine JC, Tomshine JR, Chevalier M, Mahoney JP, Steyaert J, Rasmussen SG, Sunahara RK, El-Samad H, Huang B, von Zastrow M (2013) Conformational biosensors reveal GPCR signalling from endosomes. Nature 495:534–538. https://doi.org/10.1038/nature12000
Jakobs KH, Saur W, Schultz G (1978) Inhibition of platelet adenylate cyclase by epinephrine requires GTP. FEBS Lett 85:167–170. https://doi.org/10.1016/0014-5793(78)81272-1
Jensen DD, Lieu T, Halls ML, Veldhuis NA, Imlach WL, Mai QN, Poole DP, Quach T, Aurelio L, Conner J, Herenbrink CK, Barlow N, Simpson JS, Scanlon MJ, Graham B, McCluskey A, Robinson PJ, Escriou V, Nassini R, Materazzi S, Geppetti P, Hicks GA, Christie MJ, Porter CJH, Canals M, Bunnett NW (2017) Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Sci Transl Med 9:eaal3447. https://doi.org/10.1126/scitranslmed.aal3447
Jewell-Motz EA, Liggett SB (1996) G protein-coupled receptor kinase specificity for phosphorylation and desensitization of alpha2-adrenergic receptor subtypes. J Biol Chem 271:18082–18087. https://doi.org/10.1074/jbc.271.30.18082
Joiner ML, Lise MF, Yuen EY, Kam AY, Zhang M, Hall DD, Malik ZA, Qian H, Chen Y, Ulrich JD, Burette AC, Weinberg RJ, Law PY, El-Husseini A, Yan Z, Hell JW (2010) Assembly of a beta2-adrenergic receptor--GluR1 signalling complex for localized cAMP signalling. EMBO J 29:482–495. https://doi.org/10.1038/emboj.2009.344
Jones DT, Reed RR (1989) Golf: an olfactory neuron specific-G protein involved in odorant signal transduction. Science 244:790–795. https://doi.org/10.1126/science.2499043
Jong YI, Harmon SK, O'Malley KL (2018) GPCR signalling from within the cell. Br J Pharmacol 175:4026–4035. https://doi.org/10.1111/bph.14023
Jong YJ, Kumar V, O'Malley KL (2009) Intracellular metabotropic glutamate receptor 5 (mGluR5) activates signaling cascades distinct from cell surface counterparts. J Biol Chem 284:35827–35838. https://doi.org/10.1074/jbc.M109.046276
Joyal JS, Nim S, Zhu T, Sitaras N, Rivera JC, Shao Z, Sapieha P, Hamel D, Sanchez M, Zaniolo K, St-Louis M, Ouellette J, Montoya-Zavala M, Zabeida A, Picard E, Hardy P, Bhosle V, Varma DR, Gobeil F Jr, Beauséjour C, Boileau C, Klein W, Hollenberg M, Ribeiro-da-Silva A, Andelfinger G, Chemtob S (2014) Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis. Nat Med 20:1165–1173. https://doi.org/10.1038/nm.3669
Keyes J, Ganesan A, Molinar-Inglis O, Hamidzadeh A, Zhang J, Ling M, Trejo J, Levchenko A, Zhang J (2020) Signaling diversity enabled by Rap1-regulated plasma membrane ERK with distinct temporal dynamics. Elife 9:e57410. https://doi.org/10.7554/eLife.57410
Kienitz M-C, Vladimirova D, Müller C, Pott L, Rinne A (2016) Receptor species-dependent desensitization controls KCNQ1/KCNE1 K+ channels as downstream effectors of Gq protein-coupled receptors. J Biol Chem 291:26410–26426. https://doi.org/10.1074/jbc.M116.746974
Kim H, Lee HN, Choi J, Seong J (2021) Spatiotemporal characterization of GPCR activity and function during endosomal trafficking pathway. Anal Chem 93:2010–2017. https://doi.org/10.1021/acs.analchem.0c03323
Kwon Y, Mehta S, Clark M, Walters G, Zhong Y, Lee HN, Sunahara RK, Zhang J (2022) Non-canonical β-adrenergic activation of ERK at endosomes. Nature 611(7934):173–179. https://doi.org/10.1038/s41586-022-05343-3. Epub 2022 Oct 26. PMID: 36289326; PMCID: PMC10031817
Lee D, Robeva A, Chen Z, Minneman KP (2003) Mutational uncoupling of α1A-adrenergic receptors from G proteins also uncouples mitogenic and transcriptional responses in PC12 cells. J Pharmacol Exp Ther 306:471–477. https://doi.org/10.1124/jpet.103.050500
Lemire I, Allen BG, Rindt H, Hebert TE (1998) Cardiac-specific overexpression of alpha1B-AR regulates beta-AR activity via molecular crosstalk. J Mol Cell Cardiol 30:1827–1839. https://doi.org/10.1006/jmcc.1998.0746
Li L, Cai H, Liu H, Guo T (2015) β-Adrenergic stimulation activates protein kinase Cε and induces extracellular signal-regulated kinase phosphorylation and cardiomyocyte hypertrophy. Mol Med Rep 11:4373–4380. https://doi.org/10.3892/mmr.2015.3316
Li L, Desantiago J, Chu G, Kranias EG, Bers DM (2000) Phosphorylation of phospholamban and troponin I in β-adrenergic-induced acceleration of cardiac relaxation. Am J Physiol Heart Circ Physiol 278:H769–H779. https://doi.org/10.1152/ajpheart.2000.278.3.H769
Li Y, Dillon TJ, Takahashi M, Earley KT, Stork PJS (2016) Protein kinase A-independent Ras protein activation cooperates with Rap1 protein to mediate activation of the extracellular signal-regulated kinases (ERK) by cAMP. J Biol Chem 291:21584–21595. https://doi.org/10.1074/jbc.M116.730978
Li Y, Takahashi M, Stork PJS (2013) Ras-mutant cancer cells display B-Raf binding to Ras that activates extracellular signal-regulated kinase and is inhibited by protein kinase A phosphorylation. J Biol Chem 288:27646–27657. https://doi.org/10.1074/jbc.M113.463067
Limbird LE, Gill DM, Lefkowitz RJ (1980) Agonist-promoted coupling of the beta-adrenergic receptor with the guanine nucleotide regulatory protein of the adenylate cyclase system. Proc Natl Acad Sci U S A 77:775–779. https://doi.org/10.1073/pnas.77.2.775
Lindemann JP, Jones LR, Hathaway DR, Henry BG, Watanabe AM (1983) Beta-adrenergic stimulation of phospholamban phosphorylation and Ca2+-ATPase activity in Guinea pig ventricles. J Biol Chem 258:464–471
Liu F, He K, Yang X, Xu N, Liang Z, Xu M, Zhao X, Han Q, Zhang Y (2011) α1A-adrenergic receptor induces activation of extracellular signal-regulated kinase 1/2 through endocytic pathway. PloS One 6:e21520. https://doi.org/10.1371/journal.pone.0021520
Liu G, Papa A, Katchman AN, Zakharov SI, Roybal D, Hennessey JA, Kushner J, Yang L, Chen B-X, Kushnir A, Dangas K, Gygi SP, Pitt GS, Colecraft HM, Ben-Johny M, Kalocsay M, Marx SO (2020) Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics. Nature 577:695–700. https://doi.org/10.1038/s41586-020-1947-z
Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ (1990) β-Arrestin: a protein that regulates β-adrenergic receptor function. Science 248(4962):1547–1550. https://doi.org/10.1126/science.2163110. PMID: 2163110
Lukasheva V, Devost D, Le Gouill C, Namkung Y, Martin RD, Longpré JM, Amraei M, Shinjo Y, Hogue M, Lagacé M, Breton B, Aoki J, Tanny JC, Laporte SA, Pineyro G, Inoue A, Bouvier M, Hébert TE (2020) Signal profiling of the β(1)AR reveals coupling to novel signalling pathways and distinct phenotypic responses mediated by β(1)AR and β(2)AR. Sci Rep 10:8779. https://doi.org/10.1038/s41598-020-65636-3
Luttrell LM, Lefkowitz RJ (2002) The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 115:455–465. https://doi.org/10.1242/jcs.115.3.455
Luttrell LM, Wang J, Plouffe B, Smith JS, Yamani L, Kaur S, Jean-Charles P-Y, Gauthier C, Lee M-H, Pani B, Kim J, Ahn S, Rajagopal S, Reiter E, Bouvier M, Shenoy SK, Laporte SA, Rockman HA, Lefkowitz RJ (2018) Manifold roles of beta-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9. Sci Signal 11:eaat7650. https://doi.org/10.1126/scisignal.aat7650
Ma YC, Huang J, Ali S, Lowry W, Huang XY (2000) Src tyrosine kinase is a novel direct effector of G proteins. Cell 102:635–646. https://doi.org/10.1016/s0092-8674(00)00086-6
MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4:566–577. https://doi.org/10.1038/nrm1151
Mai QN, Shenoy P, Quach T, Retamal JS, Gondin AB, Yeatman HR, Aurelio L, Conner JW, Poole DP, Canals M, Nowell CJ, Graham B, Davis TP, Briddon SJ, Hill SJ, Porter CJH, Bunnett NW, Halls ML, Veldhuis NA (2021) A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes. J Biol Chem 296:100345. https://doi.org/10.1016/j.jbc.2021.100345
Man KNM, Navedo MF, Horne MC, Hell JW (2020) β(2) adrenergic receptor complexes with the L-type Ca(2+) channel Ca(V)1.2 and AMPA-type glutamate receptors: paradigms for pharmacological targeting of protein interactions. Annu Rev Pharmacol Toxicol 60:155–174. https://doi.org/10.1146/annurev-pharmtox-010919-023404
Marx SO, Ondrias K, Marks AR (1998) Coupled gating between individual skeletal muscle Ca2+ release channels (ryanodine receptors). Science 281:818–821. https://doi.org/10.1126/science.281.5378.818
Masuho I, Ostrovskaya O, Kramer GM, Jones CD, Xie K, Martemyanov KA (2015) Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors. Sci Signal 8:ra123. https://doi.org/10.1126/scisignal.aab4068
Michel MC, Brass LF, Williams A, Bokoch GM, LaMorte VJ, Motulsky HJ (1989) Alpha 2-adrenergic receptor stimulation mobilizes intracellular Ca2+ in human erythroleukemia cells. J Biol Chem 264:4986–4991
Milligan G, Rees S (1999) Chimaeric Gα proteins: their potential use in drug discovery. Trends Pharmacol Sci 20:118–124. https://doi.org/10.1016/S0165-6147(99)01320-6
Mongillo M, McSorley T, Evellin S, Sood A, Lissandron V, Terrin A, Huston E, Hannawacker A, Lohse MJ, Pozzan T, Houslay MD, Zaccolo M (2004) Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases. Circ Res 95:67–75. https://doi.org/10.1161/01.Res.0000134629.84732.11
Moniotte S, Kobzik L, Feron O, Trochu J-N, Gauthier C, Balligand J-L (2001) Upregulation of beta3-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation 103:1649–1655. https://doi.org/10.1161/01.CIR.103.12.1649
Moore RH, Sadovnikoff N, Hoffenberg S, Liu S, Woodford P, Angelides K, Trial JA, Carsrud ND, Dickey BF, Knoll BJ (1995) Ligand-stimulated beta 2-adrenergic receptor internalization via the constitutive endocytic pathway into rab5-containing endosomes. J Cell Sci 108(Pt 9):2983–2991. https://doi.org/10.1242/jcs.108.9.2983
Mueed I, Bains P, Zhang L, Macleod KM (2004) Differential participation of protein kinase C and Rho kinase in alpha 1-adrenoceptor mediated contraction in rat arteries. Can J Physiol Pharmacol 82:895–902. https://doi.org/10.1139/y04-086
Murphy GJ, Kirkham DM, Cawthorne MA, Young P (1993) Correlation of β3-adrenoceptor-induced activation of cyclic amp-dependent protein kinase with activation of lipolysis in rat white adipocytes. Biochem Pharmacol 46:575–581. https://doi.org/10.1016/0006-2952(93)90540-D
Myagmar B-E, Flynn JM, Cowley PM, Swigart PM, Montgomery MD, Thai K, Nair D, Gupta R, Deng DX, Hosoda C, Melov S, Baker AJ, Simpson PC (2017) Adrenergic receptors in individual ventricular myocytes. Circ Res 120:1103–1115. https://doi.org/10.1161/CIRCRESAHA.117.310520
Nagiri C, Kobayashi K, Tomita A, Kato M, Kobayashi K, Yamashita K, Nishizawa T, Inoue A, Shihoya W, Nureki O (2021) Cryo-EM structure of the β3-adrenergic receptor reveals the molecular basis of subtype selectivity. Mol Cell 81:3205–3215.e3205. https://doi.org/10.1016/j.molcel.2021.06.024
Nash CA, Wei W, Irannejad R, Smrcka AV (2019) Golgi localized beta1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCepsilon to regulate cardiac hypertrophy. Elife 8:e48167. https://doi.org/10.7554/eLife.48167
Nasman J, Kukkonen JP, Ammoun S, Akerman KE (2001) Role of G-protein availability in differential signaling by alpha 2-adrenoceptors. Biochem Pharmacol 62:913–922. https://doi.org/10.1016/s0006-2952(01)00730-4
Ngala RA, O'Dowd J, Wang SJ, Agarwal A, Stocker C, Cawthorne MA, Arch JR (2008) Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and beta2-adrenoceptor mechanisms. Br J Pharmacol 155:395–406. https://doi.org/10.1038/bjp.2008.244
Ngala RA, O'Dowd J, Wang SJ, Stocker C, Cawthorne MA, Arch JR (2009) Beta2-adrenoceptors and non-beta-adrenoceptors mediate effects of BRL37344 and clenbuterol on glucose uptake in soleus muscle: studies using knockout mice. Br J Pharmacol 158:1676–1682. https://doi.org/10.1111/j.1476-5381.2009.00472.x
Niemeyer A, Rinne A, Kienitz M-C (2019) Receptor-specific regulation of atrial GIRK channel activity by different Ca2+-dependent PKC isoforms. Cell Signal 64:109418. https://doi.org/10.1016/j.cellsig.2019.109418
Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J (2010) Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327:1653–1657. https://doi.org/10.1126/science.1185988
O'Connell TD, Jensen BC, Baker AJ, Simpson PC (2014) Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 66:308–333. https://doi.org/10.1124/pr.112.007203
O'Hayre M, Eichel K, Avino S, Zhao X, Steffen DJ, Feng X, Kawakami K, Aoki J, Messer K, Sunahara R, Inoue A, von Zastrow M, Gutkind JS (2017) Genetic evidence that β-arrestins are dispensable for the initiation of β(2)-adrenergic receptor signaling to ERK. Sci Signal 10:eaal3395. https://doi.org/10.1126/scisignal.aal3395
Obara Y, Labudda K, Dillon TJ, Stork PJS (2004) PKA phosphorylation of Src mediates Rap1 activation in NGF and cAMP signaling in PC12 cells. J Cell Sci 117:6085–6094. https://doi.org/10.1242/jcs.01527
Oestreich EA, Wang H, Malik S, Kaproth-Joslin KA, Blaxall BC, Kelley GG, Dirksen RT, Smrcka AV (2007) Epac-mediated activation of phospholipase C epsilon plays a critical role in beta-adrenergic receptor-dependent enhancement of Ca2+ mobilization in cardiac myocytes. J Biol Chem 282:5488–5495. https://doi.org/10.1074/jbc.M608495200
Okeke K, Angers S, Bouvier M, Michel MC (2019) Agonist-induced desensitisation of β(3) -adrenoceptors: where, when, and how? Br J Pharmacol 176:2539–2558. https://doi.org/10.1111/bph.14633
Oleksa LM, Hool LC, Harvey RD (1996) Alpha1-adrenergic inhibition of the beta-adrenergically activated Cl- current in Guinea pig ventricular myocytes. Circ Res 78:1090–1099. https://doi.org/10.1161/01.RES.78.6.1090
Olsen RHJ, DiBerto JF, English JG, Glaudin AM, Krumm BE, Slocum ST, Che T, Gavin AC, McCorvy JD, Roth BL, Strachan RT (2020) TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat Chem Biol 16:841–849. https://doi.org/10.1038/s41589-020-0535-8
Oude Weernink PA, Han L, Jakobs KH, Schmidt M (2007) Dynamic phospholipid signaling by G protein-coupled receptors. Biochim Biophys Acta Biomembr 1768:888–900. https://doi.org/10.1016/j.bbamem.2006.09.012
Papa A, Kushner J, Marx SO (2022) Adrenergic regulation of calcium channels in the heart. Annu Rev Physiol 84:285–306. https://doi.org/10.1146/annurev-physiol-060121-041653
Penela P, Ribas C, Sánchez-Madrid F, Mayor F (2019) G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub. Cell Mol Life Sci 76:4423–4446. https://doi.org/10.1007/s00018-019-03274-3
Perez DM (2020) α1-adrenergic receptors in neurotransmission, synaptic plasticity, and cognition. Front Pharmacol 11:581098. https://doi.org/10.3389/fphar.2020.581098
Pérez López I, Cariolato L, Maric D, Gillet L, Abriel H, Diviani D (2013) A-kinase anchoring protein Lbc coordinates a p38 activating signaling complex controlling compensatory cardiac hypertrophy. Mol Cell Biol 33:2903–2917. https://doi.org/10.1128/mcb.00031-13
Perez-Aso M, Segura V, Montó F, Barettino D, Noguera MA, Milligan G, D'Ocon P (2013) The three α1-adrenoceptor subtypes show different spatio-temporal mechanisms of internalization and ERK1/2 phosphorylation. Biochim Biophys Acta 1833:2322–2333. https://doi.org/10.1016/j.bbamcr.2013.06.013
Proudman RGW, Akinaga J, Baker JG (2022) The signaling and selectivity of α-adrenoceptor agonists for the human α2A, α2B and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors. Pharmacol Res Perspect 10:e01003. https://doi.org/10.1002/prp2.1003
Qian H, Matt L, Zhang M, Nguyen M, Patriarchi T, Koval OM, Anderson ME, He K, Lee HK, Hell JW (2012) β2-adrenergic receptor supports prolonged theta tetanus-induced LTP. J Neurophysiol 107:2703–2712. https://doi.org/10.1152/jn.00374.2011
Qian H, Patriarchi T, Price JL, Matt L, Lee B, Nieves-Cintrón M, Buonarati OR, Chowdhury D, Nanou E, Nystoriak MA, Catterall WA, Poomvanicha M, Hofmann F, Navedo MF, Hell JW (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. https://doi.org/10.1126/scisignal.aaf9659
Rapacciuolo A, Suvarna S, Barki-Harrington L, Luttrell LM, Cong M, Lefkowitz RJ, Rockman HA (2003) Protein kinase A and G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis through different pathways. J Biol Chem 278:35403–35411. https://doi.org/10.1074/jbc.M305675200
Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK (2011) Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477:549–555. https://doi.org/10.1038/nature10361
Reiken S, Lacampagne A, Zhou H, Kherani A, Lehnart SE, Ward C, Huang F, Gaburjakova M, Gaburjakova J, Rosemblit N, Warren MS, He K-l, Yi G-h, Wang J, Burkhoff D, Vassort G, Marks AR (2003) PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle : defective regulation in heart failure. J Cell Biol 160:919–928. https://doi.org/10.1083/jcb.200211012
Renkhold L, Kollmann R, Inderwiedenstraße L, Kienitz M-C (2022) PKC-isoform specific regulation of receptor desensitization and KCNQ1/KCNE1 K+ channel activity by mutant α1B-adrenergic receptors. Cell Signal 91:110228. https://doi.org/10.1016/j.cellsig.2021.110228
Rosas PC, Liu Y, Abdalla MI, Thomas CM, Kidwell DT, Dusio GF, Mukhopadhyay D, Kumar R, Baker KM, Mitchell BM, Powers PA, Fitzsimons DP, Patel BG, Warren CM, Solaro RJ, Moss RL, Tong CW (2015) Phosphorylation of cardiac myosin-binding protein-C is a critical mediator of diastolic function. Circ Heart Fail 8:582–594. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001550
Sabol SL, Nirenberg M (1979) Regulation of adenylate cyclase of neuroblastoma x glioma hybrid cells by alpha-adrenergic receptors. I. Inhibition of adenylate cyclase mediated by alpha receptors. J Biol Chem 254:1913–1920
Sabri A, Pak E, Alcott SA, Wilson BA, Steinberg SF (2000) Coupling function of endogenous alpha1- and beta-adrenergic receptors in mouse cardiomyocytes. Circ Res 86:1047–1053. https://doi.org/10.1161/01.RES.86.10.1047
Salm AK, McCarthy KD (1990) Norepinephrine-evoked calcium transients in cultured cerebral type 1 astroglia. Glia 3:529–538. https://doi.org/10.1002/glia.440030612
Schleicher K, Zaccolo M (2018) Using cAMP sensors to study cardiac nanodomains. J Cardiovasc Dev Dis 5:17. https://doi.org/10.3390/jcdd5010017
Schmidt M, Evellin S, Weernink PAO, Fv D, Rehmann H, Lomasney JW, Jakobs KH (2001) A new phospholipase-C–calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat Cell Biol 3:1020–1024. https://doi.org/10.1038/ncb1101-1020
Schmitt JM, Stork PJ (2002) PKA phosphorylation of Src mediates cAMP’s inhibition of cell growth via Rap1. Mol Cell 9:85–94. https://doi.org/10.1016/s1097-2765(01)00432-4
Schmitt JM, Stork PJS (2000) Beta2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf. J Biol Chem 275:25342–25350. https://doi.org/10.1074/jbc.M003213200
Shah S, Brock EJ, Ji K, Mattingly RR (2019) Ras and Rap1: a tale of two GTPases. Semin Cancer Biol 54:29–39. https://doi.org/10.1016/j.semcancer.2018.03.005
Shenoy SK, Lefkowitz RJ (2011) β-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci 32:521–533. https://doi.org/10.1016/j.tips.2011.05.002
Soave M, Stoddart LA, White CW, Kilpatrick LE, Goulding J, Briddon SJ, Hill SJ (2021) Detection of genome-edited and endogenously expressed G protein-coupled receptors. FEBS J 288:2585–2601. https://doi.org/10.1111/febs.15729
Soini SL, Duzic E, Lanier SM, Åkerman KEO (1997) Dual modulation of calcium channel current via recombinant α2-adrenoceptors in pheochromocytoma (PC-12) cells. Pflugers Arch 435:280–285. https://doi.org/10.1007/s004240050513
Stork PJ, Schmitt JM (2002) Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 12:258–266. https://doi.org/10.1016/s0962-8924(02)02294-8
Su M, Zhu L, Zhang Y, Paknejad N, Dey R, Huang J, Lee M-Y, Williams D, Jordan KD, Eng ET, Ernst OP, Meyerson JR, Hite RK, Walz T, Liu W, Huang X-Y (2020) Structural basis of the activation of heterotrimeric Gs-protein by isoproterenol-bound β1-adrenergic receptor. Mol Cell 80:59–71.e54. https://doi.org/10.1016/j.molcel.2020.08.001
Su M, Wang J, Xiang G et al (2023) Structural basis of agonist specificity of α1A-adrenergic receptor. Nat Commun 14:4819. https://doi.org/10.1038/s41467-023-40524-2
Takahashi M, Dillon TJ, Liu C, Kariya Y, Wang Z, Stork PJS (2013) Protein kinase A-dependent phosphorylation of Rap1 regulates its membrane localization and cell migration. J Biol Chem 288:27712–27723. https://doi.org/10.1074/jbc.M113.466904
Takahashi M, Li Y, Dillon TJ, Stork PJS (2017) Phosphorylation of Rap1 by cAMP-dependent protein kinase (PKA) creates a binding site for KSR to sustain ERK activation by cAMP. J Biol Chem 292:1449–1461. https://doi.org/10.1074/jbc.M116.768986
Toyoda Y, Zhu A, Kong F et al (2023) Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody. Nat Commun 14:3655. https://doi.org/10.1038/s41467-023-39310-x
Tsvetanova NG, Trester-Zedlitz M, Newton BW, Peng GE, Johnson JR, Jimenez-Morales D, Kurland AP, Krogan NJ, von Zastrow M (2021) Endosomal cAMP production broadly impacts the cellular phosphoproteome. J Biol Chem 297:100907. https://doi.org/10.1016/j.jbc.2021.100907
Tsvetanova NG, von Zastrow M (2014) Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis. Nat Chem Biol 10:1061–1065. https://doi.org/10.1038/nchembio.1665
Vossler MR, Yao H, York RD, Pan M-G, Rim CS, Stork PJS (1997) cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89:73–82. https://doi.org/10.1016/S0092-8674(00)80184-1
Wan Y, Huang X-Y (1998) Analysis of the Gs/mitogen-activated protein kinase pathway in mutant S49 cells. J Biol Chem 273:14533–14537. https://doi.org/10.1074/jbc.273.23.14533
Wang Q, Lu R, Zhao J, Limbird LE (2006a) Arrestin serves as a molecular switch, linking endogenous alpha2-adrenergic receptor to Src-dependent, but not Src-independent, ERK activation. J Biol Chem 281:25948–25955. https://doi.org/10.1074/jbc.M605415200
Wang Z, Dillon TJ, Pokala V, Mishra S, Labudda K, Hunter B, Stork PJS (2006b) Rap1-mediated activation of extracellular signal-regulated kinases by cyclic AMP is dependent on the mode of Rap1 activation. Mol Cell Biol 26:2130–2145. https://doi.org/10.1128/MCB.26.6.2130-2145.2006
Wehrens XHT, Lehnart SE, Marks AR (2005) Intracellular calcium release and cardiac disease. Annu Rev Physiol 67:69–98. https://doi.org/10.1146/annurev.physiol.67.040403.114521
Weinberg ZY, Puthenveedu MA (2019) Regulation of G protein-coupled receptor signaling by plasma membrane organization and endocytosis. Traffic 20:121–129. https://doi.org/10.1111/tra.12628
White JA, McKinney BC, John MC, Powers PA, Kamp TJ, Murphy GG (2008) Conditional forebrain deletion of the L-type calcium channel Ca V 1.2 disrupts remote spatial memories in mice. Learn Mem 15:1–5. https://doi.org/10.1101/lm.773208
Willette BKA, Zhang JF, Zhang J, Tsvetanova NG (2023) Endosome positioning coordinates spatially selective GPCR signaling. Nat Chem Biol. https://doi.org/10.1038/s41589-023-01390-7. Epub ahead of print. PMID: 37500769
Wright CD, Chen Q, Baye NL, Huang Y, Healy CL, Kasinathan S, O'Connell TD (2008) Nuclear alpha1-adrenergic receptors signal activated ERK localization to caveolae in adult cardiac myocytes. Circ Res 103:992–1000. https://doi.org/10.1161/circresaha.108.176024
Wright CD, Wu SC, Dahl EF, Sazama AJ, O'Connell TD (2012) Nuclear localization drives α1-adrenergic receptor oligomerization and signaling in cardiac myocytes. Cell Signal 24:794–802. https://doi.org/10.1016/j.cellsig.2011.11.014
Wu D, Katz A, Lee CH, Simon MI (1992) Activation of phospholipase C by alpha 1-adrenergic receptors is mediated by the alpha subunits of Gq family. J Biol Chem 267:25798–25802
Wu D, Kuang Y, Wu Y, Jiang H (1995) Selective coupling of beta 2-adrenergic receptor to hematopoietic-specific G proteins. J Biol Chem 270:16008–16010. https://doi.org/10.1074/jbc.270.27.16008
Wu SC, Dahl EF, Wright CD, Cypher AL, Healy CL, O'Connell TD (2014) Nuclear localization of alpha1A-adrenergic receptors is required for signaling in cardiac myocytes: an “inside-out” alpha1-AR signaling pathway. J Am Heart Assoc 3:e000145. https://doi.org/10.1161/JAHA.113.000145
Xu J et al (2022) Structural insights into ligand recognition, activation, and signaling of the α2A adrenergic receptor. Sci Adv 8:eabj5347. https://doi.org/10.1126/sciadv.abj5347
Yang Z, Kirton HM, MacDougall DA, Boyle JP, Deuchars J, Frater B, Ponnambalam S, Hardy ME, White E, Calaghan SC, Peers C, Steele DS (2015) The Golgi apparatus is a functionally distinct Ca2+ store regulated by the PKA and Epac branches of the β1-adrenergic signaling pathway. Sci Signal 8:ra101. https://doi.org/10.1126/scisignal.aaa7677
Yuan D, Liu Z, Kaindl J, Maeda S, Zhao J, Sun X, Xu J, Gmeiner P, Wang HW, Kobilka BK (2020) Activation of the α(2B) adrenoceptor by the sedative sympatholytic dexmedetomidine. Nat Chem Biol 16:507–512. https://doi.org/10.1038/s41589-020-0492-2
Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715. https://doi.org/10.1126/science.1069982
Zhang X, Odom DT, Koo S-H, Conkright MD, Canettieri G, Best J, Chen H, Jenner R, Herbolsheimer E, Jacobsen E, Kadam S, Ecker JR, Emerson B, Hogenesch JB, Unterman T, Young RA, Montminy M (2005) Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc Natl Acad Sci U S A 102:4459–4464. https://doi.org/10.1073/pnas.0501076102
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Mastos, C., Xu, X., Keen, A.C., Halls, M.L. (2024). Signalling of Adrenoceptors: Canonical Pathways and New Paradigms. In: Handbook of Experimental Pharmacology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/164_2023_704
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