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• W3036711312 abstract "G protein–coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. Very important to human medicine, GPCRs are targeted by about 35% of prescription drugs. GPCRs are characterized by a seven-transmembrane α-helical structure, transmitting extracellular signals into cells to regulate major physiological processes via heterotrimeric G proteins and β-arrestins. Initially viewed as receptors whose signaling via G proteins is delimited to the plasma membrane, it is now recognized that GPCRs signal also at various intracellular locations, and the mechanisms and (patho)physiological relevance of such signaling modes are actively investigated. The propensity of GPCRs to adopt different signaling modes is largely encoded in the structural plasticity of the receptors themselves and of their signaling complexes. Here, we review emerging modes of GPCR signaling via endosomal membranes and the physiological implications of such signaling modes. We further summarize recent structural insights into mechanisms of GPCR activation and signaling. We particularly emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism and discuss the recently uncovered and important roles of lipids in these processes. G protein–coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. Very important to human medicine, GPCRs are targeted by about 35% of prescription drugs. GPCRs are characterized by a seven-transmembrane α-helical structure, transmitting extracellular signals into cells to regulate major physiological processes via heterotrimeric G proteins and β-arrestins. Initially viewed as receptors whose signaling via G proteins is delimited to the plasma membrane, it is now recognized that GPCRs signal also at various intracellular locations, and the mechanisms and (patho)physiological relevance of such signaling modes are actively investigated. The propensity of GPCRs to adopt different signaling modes is largely encoded in the structural plasticity of the receptors themselves and of their signaling complexes. Here, we review emerging modes of GPCR signaling via endosomal membranes and the physiological implications of such signaling modes. We further summarize recent structural insights into mechanisms of GPCR activation and signaling. We particularly emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism and discuss the recently uncovered and important roles of lipids in these processes. Cells sense their environment through the plasma membrane–embedded receptors, which capture external stimuli and convert them to intracellular signaling cascades leading to appropriate cellular responses (e.g. proliferation, differentiation, death) and subsequent physiological outcomes. G protein–coupled receptors (GPCRs) comprise the largest family of cell membrane receptors and recognize a broad spectrum of ligands ranging from photons to large protein molecules. GPCRs regulate many physiological processes in body systems, such as the skeletal, muscular, nervous, endocrine, urinary, and digestive systems among others. Due to their key role in human physiology, malfunctions of GPCRs cause severe diseases, and GPCRs are thus attractive pharmaceutical targets. They constitute the largest family of proteins targeted by currently approved drugs; ∼700 currently approved marketed drugs (or about 35%) target GPCRs (1Sriram K. Insel P.A. G protein-coupled receptors as targets for approved drugs: how many targets and how many drugs?.Mol. Pharmacol. 2018; 93 (29298813): 251-25810.1124/mol.117.111062Crossref PubMed Scopus (258) Google Scholar), and these numbers are likely to further increase because of intensive research efforts in GPCR druggability (2Hauser A.S. Attwood M.M. Rask-Andersen M. Schiöth H.B. Gloriam D.E. Trends in GPCR drug discovery: new agents, targets and indications.Nat. Rev. Drug Discov. 2017; 16 (29075003): 829-84210.1038/nrd.2017.178Crossref PubMed Scopus (687) Google Scholar). Signal transduction via a GPCR starts when ligand binding to the receptor triggers or stabilizes an active receptor conformation, permitting coupling to heterotrimeric guanine nucleotide–binding proteins (G proteins), which are composed of three distinct α, β, and γ subunits. There are five subtypes of Gβ subunits and 12 subtypes of Gγ subunits that form constitutive Gβγ heterodimers. Based on sequence homology of the Gα subunits, the G proteins are classified into four subfamilies: Gs (Gαs and Gαolf), Gi (Gαi1–3, Gαo, GαZ, and Gαt), Gq (Gαq, Gα11, and Gα14–15), and G12 (Gα12 and Gα13) (3Cabrera-Vera T.M. Vanhauwe J. Thomas T.O. Medkova M. Preininger A. Mazzoni M.R. Hamm H.E. Insights into G protein structure, function, and regulation.Endocr. Rev. 2003; 24 (14671004): 765-78110.1210/er.2000-0026Crossref PubMed Scopus (482) Google Scholar), each of which affect distinct downstream effectors (Fig. 1). Binding with the active state of the receptor induces a rapid conformational change in G proteins catalyzing the exchange of GDP for GTP on the Gα subunit, resulting in the dissociation or rearrangement between the GTP-bound Gα and Gβγ subunits (4Neer E.J. Clapham D.E. Roles of G protein subunits in transmembrane signalling.Nature. 1988; 333 (3130578): 129-13410.1038/333129a0Crossref PubMed Google Scholar, 5Janetopoulos C. Jin T. Devreotes P. Receptor-mediated activation of heterotrimeric G-proteins in living cells.Science. 2001; 291 (11264536): 2408-241110.1126/science.1055835Crossref PubMed Scopus (356) Google Scholar, 6Bünemann M. Frank M. Lohse M.J. Gi protein activation in intact cells involves subunit rearrangement rather than dissociation.Proc. Natl. Acad. Sci. U. S. A. 2003; 100 (14673086): 16077-1608210.1073/pnas.2536719100Crossref PubMed Scopus (303) Google Scholar). Both Gα-GTP and Gβγ independently regulate the activity of diverse effectors (Fig. 1), such as transmembrane adenylate cyclases via Gαs to convert ATP into cAMP and then initiate protein kinase A (PKA)- and exchange protein directly activated by cAMP (Epac; a cAMP-regulated guanine nucleotide exchange protein for small GTPase Rap1)-dependent signaling pathways, phospholipase Cβ (PLCβ) via Gαq to hydrolyze phosphatidylinositol (4,5)-bisphosphate (PIP2) into diacylglycerol (DAG), and inositol (1,4,5)-trisphosphate (IP3) to release stored Ca2+ and activate protein kinase C (PKC), and/or channels such as G protein–activated inwardly rectifying K+ (GIRK) channels via Gβγ, resulting in cell membrane hyperpolarization. Once activated, the duration of G protein signaling depends on the intrinsic GTPase activity of Gα, which hydrolyzes GTP to GDP and leads to the recovery of the inactive form of the heterotrimer Gαβγ, prompting a new activation cycle. The time constant of the intrinsic GTPase reaction is slow (10–60 s) and accelerated by regulators of G protein signaling acting as GTPase-activating proteins (7De Vries L. Zheng B. Fischer T. Elenko E. Farquhar M.G. The regulator of G protein signaling family.Annu. Rev. Pharmacol. Toxicol. 2000; 40 (10836135): 235-27110.1146/annurev.pharmtox.40.1.235Crossref PubMed Scopus (491) Google Scholar). Initially, GPCRs were viewed as signaling through G proteins exclusively at the plasma membrane. In this long-standing view, the agonist-induced receptor activation is rapidly terminated through receptor phosphorylation by GPCR kinases (GRKs), permitting recruitment of cytosolic β-arrestins and subsequent receptor internalization to endosomes for either redistribution of receptors to lysosomes for degradation or recycling to the cell surface, thus enabling receptor resensitization. During the last decade, this paradigm has been shifted by findings revealing an alternative mode of GPCR signaling and function via G proteins in various intracellular compartments, including early endosomes (Fig. 2A), Golgi, mitochondria, endoplasmic reticulum (ER), and nucleus (reviewed in Refs. 8Jong Y.I. Harmon S.K. O'Malley K.L. GPCR signalling from within the cell.Br. J. Pharmacol. 2018; 175 (28872669): 4026-403510.1111/bph.14023Crossref PubMed Scopus (23) Google Scholar, 9Lobingier B.T. von Zastrow M. When trafficking and signaling mix: how subcellular location shapes G protein-coupled receptor activation of heterotrimeric G proteins.Traffic. 2019; 20 (30578610): 130-13610.1111/tra.12634Crossref PubMed Scopus (28) Google Scholar, 10Calebiro D. Godbole A. Internalization of G-protein-coupled receptors: implication in receptor function, physiology and diseases.Best Pract. Res. Clin. Endocrinol. Metab. 2018; 32 (29678288): 83-9110.1016/j.beem.2018.01.004Crossref PubMed Scopus (25) Google Scholar, 11Eichel K. von Zastrow M. Subcellular organization of GPCR signaling.Trends Pharmacol. Sci. 2018; 39 (29478570): 200-20810.1016/j.tips.2017.11.009Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 12Plouffe B. Thomsen A.R.B. Irannejad R. Emerging role of compartmentalized G protein-coupled receptor signaling in the cardiovascular field.ACS Pharmacol. Transl. Sci. 2020; 3 (32296764): 221-23610.1021/acsptsci.0c00006Crossref PubMed Scopus (4) Google Scholar, 13Retamal J.S. Ramirez-Garcia P.D. Shenoy P.A. Poole D.P. Veldhuis N.A. Internalized GPCRs as potential therapeutic targets for the management of pain.Front. Mol. Neurosci. 2019; 12 (31798411): 27310.3389/fnmol.2019.00273Crossref PubMed Scopus (2) Google Scholar, 14Hanyaloglu A.C. Advances in membrane trafficking and endosomal signaling of G protein-coupled receptors.Int. Rev. Cell Mol. Biol. 2018; 339 (29776606): 93-13110.1016/bs.ircmb.2018.03.001Crossref PubMed Scopus (11) Google Scholar, 15Jong Y.I. Harmon S.K. O'Malley K.L. Intracellular GPCRs play key roles in synaptic plasticity.ACS Chem. Neurosci. 2018; 9 (29409317): 2162-217210.1021/acschemneuro.7b00516Crossref PubMed Scopus (15) Google Scholar), whereas β-arrestins were discovered to have multiple functions that extend far beyond GPCR desensitization and internalization (reviewed in Refs. 16Gurevich V.V. Gurevich E.V. Plethora of functions packed into 45 kDa arrestins: biological implications and possible therapeutic strategies.Cell Mol. Life Sci. 2019; 76 (31422444): 4413-442110.1007/s00018-019-03272-5Crossref PubMed Scopus (12) Google Scholar and 17Laporte S.A. Scott M.G.H. β-Arrestins: multitask scaffolds orchestrating the where and when in cell signalling.Methods Mol. Biol. 2019; 1957 (30919345): 9-5510.1007/978-1-4939-9158-7_2Crossref PubMed Scopus (10) Google Scholar). Here we outline current knowledge of the structural basis for GPCR signaling, including the role of the lipids, with special emphasis on endosomal signaling determinants. We further discuss recent mechanistic findings on GPCR signaling from early endosomes and their (patho)physiological implications.Figure 2General principle of GPCR signaling via cAMP. A, in the classical model, production of cAMP (1st pool) only takes place at the cell membrane after activation of Gs by the agonist-bound receptors (step 1). This cAMP response is usually short-lived due to the action of phosphodiesterases and rapid receptor desensitization initiated by recruitment of GRKs and receptor phosphorylation (step 2), followed by recruitment of β-arrestin (βarr; step 3) driving receptor endocytosis and eventually engaging β-arrestin-dependent mitogen-activated protein kinase signaling cascades (step 4). In the more recent model, agonists—usually peptide hormones—that interact tightly with receptor in a conformationally dependent rather than G-protein–dependent manner, also induce sustained cAMP that originated from ligand–GPCR complexes in endosomes (2nd pool) (step 4). Endosomal cAMP production continues until endosomal acidification induces the release of the agonist from the receptor (step 5) and receptor dephosphorylation (step 6), allowing receptor degradation (step 7), receptor transfer to the Golgi apparatus (step 8), and/or the receptor recycling (step 9). B, examples of cAMP time-course profiles mediated by PTH in live cells expressing PTHR and showing plasma membrane (PM; light orange) and endosomal (Endosomes; light blue) response phases for control (black), when the receptor internalization (step 4) is blocked by either dynasore or a dominant negative mutant of dynamin (purple), or when the endosomal acidification (step 5) is blocked by bafilomycin (blue). Data represent the mean ± S.E.M.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The concept that GPCRs are capable of sustaining G protein activity during and after their internalization into endosomes stems from studies comparing how the class B parathyroid hormone (PTH) type 1 receptor (PTH1R) transmits signals into cells in response to its two agonists, PTH and PTH-related peptide (PTHrP). Back in the year 2005, it was unclear why these two peptide hormones or their bioactive and structurally similar synthetic N-terminal analogs, PTH1-34 and PTHrP1-36, bind and activate the same receptor with identical pharmacological properties but display distinct responses in clinical testing: PTH1-34 stimulates more prolonged increases in serum levels of active vitamin D (i.e. 1,25-dihydroxyvitamin D3), calcium, and bone resorption markers than does PTHrP1-36 (18Horwitz M.J. Tedesco M.B. Sereika S.M. Hollis B.W. Garcia-Ocaña A. Stewart A.F. Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers.J. Clin. Endocrinol. Metab. 2003; 88 (12679445): 1603-160910.1210/jc.2002-020773Crossref PubMed Scopus (94) Google Scholar). Initial studies show that PTH1-34 differentiates itself from PTHrP1-36 by inducing prolonged cAMP responses in cultured cells expressing either recombinant or endogenous PTH1R, which are mediated at the receptor level and not by extended bioavailability of ligands (19Horwitz M.J. Tedesco M.B. Sereika S.M. Syed M.A. Garcia-Ocaña A. Bisello A. Hollis B.W. Rosen C.J. Wysolmerski J.J. Dann P. Gundberg C. Stewart A.F. Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D.J. Bone Miner. Res. 2005; 20 (16160737): 1792-180310.1359/JBMR.050602Crossref PubMed Scopus (95) Google Scholar). Biophysical and microscopy studies in live cells showed that during the time frame of cAMP production, PTHrP1-36 action is restricted to the cell membrane, whereas the PTH1-34-bound PTH1R complex internalizes and redistributes into early endosomes where the active state of Gαs, adenylate cyclases, and cAMP production can be detected (20Ferrandon S. Feinstein T.N. Castro M. Wang B. Bouley R. Potts J.T. Gardella T.J. Vilardaga J.P. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.Nat. Chem. Biol. 2009; 5 (19701185): 734-74210.1038/nchembio.206Crossref PubMed Scopus (342) Google Scholar, 21Jean-Alphonse F.G. Wehbi V.L. Chen J. Noda M. Taboas J.M. Xiao K. Vilardaga J.P. β2-Adrenergic receptor control of endosomal PTH receptor signaling via Gβγ.Nat. Chem. Biol. 2017; 13 (28024151): 259-26110.1038/nchembio.2267Crossref PubMed Scopus (25) Google Scholar). These observations coupled to the finding that blocking PTH1R internalization prevents the sustained cAMP response mediated by PTH raised the new paradigm that PTH1R can generate cAMP from intracellular membranes and that early endosomes serve as a platform for PTH1R-mediated sustained cAMP production (Fig. 2B). The marked differences between PTH and PTHrP-mediated cAMP signaling provided a mechanistic understanding of differential biological responses induced by these two hormones. The same conclusion was concomitantly and independently reached by signaling studies of the thyroid-stimulating hormone receptor (TSHR), a Gs-coupled receptor regulating thyroid functions (22Calebiro D. Nikolaev V.O. Gagliani M.C. de Filippis T. Dees C. Tacchetti C. Persani L. Lohse M.J. Persistent cAMP-signals triggered by internalized G-protein-coupled receptors.PLoS Biol. 2009; 7 (19688034): e100017210.1371/journal.pbio.1000172Crossref PubMed Scopus (336) Google Scholar), and the sphingolipid S1P receptor (S1P1R) that internalizes and traffics in the trans-Golgi network to sustain Gi-dependent signaling mediated by FTY720, a S1P1R agonist (23Mullershausen F. Zecri F. Cetin C. Billich A. Guerini D. Seuwen K. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors.Nat. Chem. Biol. 2009; 5 (19430484): 428-43410.1038/nchembio.173Crossref PubMed Scopus (261) Google Scholar). Reported in 2009, these findings led to the revision of the classical paradigm proposing that GPCRs are only active and signal via G proteins at the plasma membrane and internalize to be degraded or recycled, and they laid the foundation for a new mode of GPCR signaling via G proteins that is maintained after internalization and relocation of ligand–GPCR complexes to intracellular membranes. A growing number of studies confirmed this paradigm for additional receptor activating the Gs or Gi pathways (Table 1) and including class A (β-adrenergic receptors, vasopressin type 2 receptor) and class B (glucagon-like peptide 1 receptor, calcitonin receptor-like receptor, and pituitary adenylate cyclase–activating polypeptide type 1 receptor) GPCRs among others. In addition, several Gq-coupled GPCRs were reported to display extended Gq/PKC signaling after internalization (33Jensen D.D. Lieu T. Halls M.L. Veldhuis N.A. Imlach W.L. Mai Q.N. Poole D.P. Quach T. Aurelio L. Conner J. Herenbrink C.K. Barlow N. Simpson J.S. Scanlon M.J. Graham B. et al.Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.Sci. Transl. Med. 2017; 9 (28566424): eaal344710.1126/scitranslmed.aal3447Crossref PubMed Scopus (71) Google Scholar, 34Yarwood R.E. Imlach W.L. Lieu T. Veldhuis N.A. Jensen D.D. Klein Herenbrink C. Aurelio L. Cai Z. Christie M.J. Poole D.P. Porter C.J.H. McLean P. Hicks G.A. Geppetti P. Halls M.L. et al.Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission.Proc. Natl. Acad. Sci. U. S. A. 2017; 114 (29087309): 12309-1231410.1073/pnas.1706656114Crossref PubMed Scopus (62) Google Scholar, 35Jimenez-Vargas N.N. Pattison L.A. Zhao P. Lieu T. Latorre R. Jensen D.D. Castro J. Aurelio L. Le G.T. Flynn B. Herenbrink C.K. Yeatman H.R. Edgington-Mitchell L. Porter C.J.H. Halls M.L. et al.Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome.Proc. Natl. Acad. Sci. U. S. A. 2018; 115 (30012612): E7438-E744710.1073/pnas.1721891115Crossref PubMed Scopus (46) Google Scholar, 39Gorvin C.M. Rogers A. Hastoy B. Tarasov A.I. Frost M. Sposini S. Inoue A. Whyte M.P. Rorsman P. Hanyaloglu A.C. Breitwieser G.E. Thakker R.V. AP2σ mutations impair calcium-sensing receptor trafficking and signaling, and show an endosomal pathway to spatially direct G-protein selectivity.Cell Rep. 2018; 22 (29420171): 1054-106610.1016/j.celrep.2017.12.089Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar); however, the endosomes contain virtually no PIP2 that is necessary for production of DAG and IP3 to activate PKC, and there is no clear evidence of active Gq in endosomes so far, prompting the necessity to confirm these observations by future studies.Table 1GPCRs that display endosomal signaling via heterotrimeric G proteinsGPCRClassEndosomal signaling pathwayPhysiological outcomeReferencePTH1RBGsCa2+ homeostasis (calcemic effects)20Ferrandon S. Feinstein T.N. Castro M. Wang B. Bouley R. Potts J.T. Gardella T.J. Vilardaga J.P. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.Nat. Chem. Biol. 2009; 5 (19701185): 734-74210.1038/nchembio.206Crossref PubMed Scopus (342) Google Scholar, 24White A.D. Fang F. Jean-Alphonse F.G. Clark L.J. An H.J. Liu H. Zhao Y. Reynolds S.L. Lee S. Xiao K. Sutkeviciute I. Vilardaga J.P. Ca2+ allostery in PTH-receptor signaling.Proc. Natl. Acad. Sci. U. S. A. 2019; 116 (30718391): 3294-329910.1073/pnas.1814670116Crossref PubMed Scopus (12) Google ScholarTSHRAGsThyroid function22Calebiro D. Nikolaev V.O. Gagliani M.C. de Filippis T. Dees C. Tacchetti C. Persani L. Lohse M.J. Persistent cAMP-signals triggered by internalized G-protein-coupled receptors.PLoS Biol. 2009; 7 (19688034): e100017210.1371/journal.pbio.1000172Crossref PubMed Scopus (336) Google ScholarS1P1RAGiIncreased chemokinetic migration of primary human umbilical vein endothelial cells23Mullershausen F. Zecri F. Cetin C. Billich A. Guerini D. Seuwen K. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors.Nat. Chem. Biol. 2009; 5 (19430484): 428-43410.1038/nchembio.173Crossref PubMed Scopus (261) Google ScholarD1RAGsND25Kotowski S.J. Hopf F.W. Seif T. Bonci A. von Zastrow M. Endocytosis promotes rapid dopaminergic signaling.Neuron. 2011; 71 (21791287): 278-29010.1016/j.neuron.2011.05.036Abstract Full Text Full Text PDF PubMed Scopus (102) Google ScholarPAC1RBGsCardiac neuron excitability, chronic pain, and anxiety-like responses26Merriam L.A. Baran C.N. Girard B.M. Hardwick J.C. May V. Parsons R.L. Pituitary adenylate cyclase 1 receptor internalization and endosomal signaling mediate the pituitary adenylate cyclase activating polypeptide-induced increase in guinea pig cardiac neuron excitability.J. Neurosci. 2013; 33 (23467377): 4614-462210.1523/JNEUROSCI.4999-12.2013Crossref PubMed Scopus (58) Google Scholar, 27May V. Parsons R.L. G protein-coupled receptor endosomal signaling and regulation of neuronal excitability and stress responses: signaling options and lessons from the PAC1 receptor.J. Cell. Physiol. 2017; 232 (27661062): 698-70610.1002/jcp.25615Crossref PubMed Scopus (22) Google ScholarGLP1RBGsPromotion of glucose-stimulated insulin secretion28Kuna R.S. Girada S.B. Asalla S. Vallentyne J. Maddika S. Patterson J.T. Smiley D.L. DiMarchi R.D. Mitra P. Glucagon-like peptide-1 receptor-mediated endosomal cAMP generation promotes glucose-stimulated insulin secretion in pancreatic β-cells.Am. J. Physiol. Endocrinol. Metab. 2013; 305 (23592482): E161-E17010.1152/ajpendo.00551.2012Crossref PubMed Scopus (75) Google ScholarV2RAGsPotentially strong antidiuretic and antinatriuretic effects29Feinstein T.N. Yui N. Webber M.J. Wehbi V.L. Stevenson H.P. King Jr., J.D. Hallows K.R. Brown D. Bouley R. Vilardaga J.P. Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin.J. Biol. Chem. 2013; 288 (23935101): 27849-2786010.1074/jbc.M112.445098Abstract Full Text Full Text PDF PubMed Scopus (111) Google ScholarCTRBGs (in response to salmon calcitonin)ND30Andreassen K.V. Hjuler S.T. Furness S.G. Sexton P.M. Christopoulos A. Nosjean O. Karsdal M.A. Henriksen K. Prolonged calcitonin receptor signaling by salmon, but not human calcitonin, reveals ligand bias.PLoS ONE. 2014; 9: e9204210.1371/journal.pone.0092042Crossref PubMed Scopus (41) Google Scholarβ2ARAShort GsND31Tsvetanova N.G. von Zastrow M. Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis.Nat. Chem. Biol. 2014; 10 (25362359): 1061-106510.1038/nchembio.1665Crossref PubMed Scopus (126) Google ScholarLHRAGsFinal maturation of a fertilizable egg in females32Lyga S. Volpe S. Werthmann R.C. Götz K. Sungkaworn T. Lohse M.J. Calebiro D. Persistent cAMP signaling by internalized LH receptors in ovarian follicles.Endocrinology. 2016; 157 (26828746): 1613-162110.1210/en.2015-1945Crossref PubMed Scopus (44) Google ScholarNK1RAGqNociception33Jensen D.D. Lieu T. Halls M.L. Veldhuis N.A. Imlach W.L. Mai Q.N. Poole D.P. Quach T. Aurelio L. Conner J. Herenbrink C.K. Barlow N. Simpson J.S. Scanlon M.J. Graham B. et al.Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.Sci. Transl. Med. 2017; 9 (28566424): eaal344710.1126/scitranslmed.aal3447Crossref PubMed Scopus (71) Google ScholarCLRBGs and GqNociception34Yarwood R.E. Imlach W.L. Lieu T. Veldhuis N.A. Jensen D.D. Klein Herenbrink C. Aurelio L. Cai Z. Christie M.J. Poole D.P. Porter C.J.H. McLean P. Hicks G.A. Geppetti P. Halls M.L. et al.Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission.Proc. Natl. Acad. Sci. U. S. A. 2017; 114 (29087309): 12309-1231410.1073/pnas.1706656114Crossref PubMed Scopus (62) Google ScholarPAR2AGqColonic nociception35Jimenez-Vargas N.N. Pattison L.A. Zhao P. Lieu T. Latorre R. Jensen D.D. Castro J. Aurelio L. Le G.T. Flynn B. Herenbrink C.K. Yeatman H.R. Edgington-Mitchell L. Porter C.J.H. Halls M.L. et al.Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome.Proc. Natl. Acad. Sci. U. S. A. 2018; 115 (30012612): E7438-E744710.1073/pnas.1721891115Crossref PubMed Scopus (46) Google ScholarCXCR4AGiCXCL12-instigated suppression of anoikis/apoptosis36English E.J. Mahn S.A. Marchese A. Endocytosis is required for CXC chemokine receptor type 4 (CXCR4)-mediated Akt activation and antiapoptotic signaling.J. Biol. Chem. 2018; 293 (29899118): 11470-1148010.1074/jbc.RA118.001872Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarMORAGiND37Stoeber M. Jullie D. Lobingier B.T. Laeremans T. Steyaert J. Schiller P.W. Manglik A. von Zastrow M. A genetically encoded biosensor reveals location bias of opioid drug action.Neuron. 2018; 98 (29754753): 963-976.e510.1016/j.neuron.2018.04.021Abstract Full Text Full Text PDF PubMed Scopus (98) Google ScholarDORAGiND37Stoeber M. Jullie D. Lobingier B.T. Laeremans T. Steyaert J. Schiller P.W. Manglik A. von Zastrow M. A genetically encoded biosensor reveals location bias of opioid drug action.Neuron. 2018; 98 (29754753): 963-976.e510.1016/j.neuron.2018.04.021Abstract Full Text Full Text PDF PubMed Scopus (98) Google ScholarADGRG2AdhesionGsND38Azimzadeh P. Talamantez-Lyburn S.C. Chang K.T. Inoue A. Balenga N. Spatial regulation of GPR64/ADGRG2 signaling by β-arrestins and GPCR kinases.Ann. N. Y. Acad. Sci. 2019; 1456 (31502283): 26-4310.1111/nyas.14227Crossref PubMed Scopus (7) Google Scholar Open table in a new tab Where does the ability of certain GPCRs to sustain G protein signaling from endosomes come from? Despite the capacity of PTH to prolong endosomal cAMP signaling via a unique receptor conformation named R0 (reviewed in Ref. 40Sutkeviciute I. Clark L.J. White A.D. Gardella T.J. Vilardaga J.P. PTH/PTHrP receptor signaling, allostery, and structures.Trends Endocrinol. Metab. 2019; 30 (31699241): 860-87410.1016/j.tem.2019.07.011Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar), our structural understanding of endosomal GPCR signaling via G proteins is incomplete. The recent development of structural approaches to study mechanisms of GPCR activation (41Thal D.M. Vuckovic Z. Draper-Joyce C.J. Liang Y.L. Glukhova A. Christopoulos A. Sexton P.M. Recent advances in the determination of G protein-coupled receptor structures.Curr. Opin. Struct. Biol. 2018; 51 (29547818): 28-3410.1016/j.sbi.2018.03.002Crossref PubMed Scopus (28) Google Scholar) via cryo-EM, which will be discussed in the following paragraphs, however, opens new possibilities to unveil the exact underpinnings of endosomal GPCR signaling. Based on amino acid sequence and functional similarities, the mammalian GPCRs are classified into five families, namely A (rhodopsin-like), B (secretin receptor-like), C (metabotropic glutamate receptor-like), F (frizzled-like), and adhesion GPCRs (aGPCRs) (Fig. 3A). All of the GPCRs share a common characteristic architecture of their transmembrane domain (TMD), which is composed of seven α-helices linked by three extracellular and three intracellular loops that form a compact bundle, and N and C termini located extracellularly and intracellularly, respectively. Owing to the technological advances of X-ray crystallography and cryo-EM, during the last 2 decades, much has been learned about the structural mechanisms underlying the GPCR signaling. Our initial perception of these receptors as simple ON/OFF switches has evolved to understanding them as highly dynamic structures capable of sampling and adopting diverse conformations, each of which mediate distinct signaling outputs. GPCRs are activated by agonist ligand binding in the orthosteric binding pocket located within the upper half of the TMD core. This binding event is relayed to cytosolic side of the receptor through allosteric interaction networks that are distinct for each GPCR class but converge in a common GPCR activation hallmark—the mobilization and outward movement of transmembrane helix 6 (TM6). The outward movement of TM6 leads to the opening of the cytosolic cavity of the GPCRs, allowing the subsequent binding and activation of the heterotrimeric G proteins. Below we summarize the recent structural and dynamic insights into activation mechanisms of members of all GPCR classes, except aGPCRs, whose structures remain unknown. We also overview structural and dynamic aspects of G protein activation and the emerging structural determinants of endosomal GPCR signaling. GPCRs are allosterically regulated proteins, whereby the extracellular agonist binding is al" @default.
• W3036711312 created "2020-06-25" @default.
• W3036711312 creator A5081576808 @default.
• W3036711312 creator A5091606567 @default.
• W3036711312 date "2020-08-01" @default.
• W3036711312 modified "2023-10-18" @default.
• W3036711312 title "Structural insights into emergent signaling modes of G protein–coupled receptors" @default.
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