Functional diversification of cell signaling by GPCR localization

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(3), P. 105668 - 105668

Published: Jan. 23, 2024

G protein-coupled receptors (GPCRs) are the largest family of cell surface and a critical class regulators mammalian physiology. Also known as seven transmembrane (7TMs), GPCRs ubiquitously expressed versatile, detecting diverse set endogenous stimuli, including odorants, neurotransmitters, hormones, peptides, lipids. Accordingly, have emerged drug targets, accounting for upward 30% all prescription drugs. The view that ligand-induced GPCR responses originate exclusively from has evolved to reflect accumulating evidence can elicit additional waves signaling intracellular compartments. These events in turn shape unique cellular physiological outcomes. Here, we discuss our current understanding roles regulation compartmentalized signaling. classical had been takes place at (1Sriram K. Insel P.A. targets approved drugs: how many drugs?.Mol. Pharmacol. 2018; 93: 251-258Google Scholar). agonist-bound receptor undergoes conformational change promotes activation heterotrimeric protein complex, Gαβγ. proteins classified into four main families according their Gα subunit. Gαs Gαi/o interact with adenylyl cyclase enzymes stimulate or inhibit production cyclic AMP (cAMP), respectively. Gαq activates mobilization calcium via phospholipase C (PLC), while Gα12/13 signals vias Rho GTPase stimulation. second messengers initiate cascades lead key kinases transcription factors coordinate response. For instance, cAMP kinase A (PKA). Following ligand binding, post-translational modifications, phosphorylation its loops and/or C-terminal tail by (GRKs) (2Gurevich V.V. Gurevich E.V. regulation: role GRKs arrestins.Front. 2019; 10: 125Google This facilitates recruitment β-arrestins one 2. Classically, association arrestins was presumed terminate two ways: sterically hindering interactions promoting internalization through scaffolding AP2 adaptor complex clathrin Scholar, 3Lohse M.J. Benovic J.L. Codina J. Caron M.G. Lefkowitz R.J. beta-Arrestin: regulates beta-adrenergic function.Science. 1990; 248: 1547-1550Google 4Cahill 3rd, T.J. Thomsen A.R. Tarrasch J.T. Plouffe B. Nguyen A.H. Yang F. et al.Distinct conformations GPCR-β-arrestin complexes mediate desensitization, signaling, endocytosis.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 2562-2567Google Subsequently, internalized is sorted degraded lysosome recycled back plasma membrane cycles (Fig. 1A). traditional model undergone significant revision past 2 decades highlights immense complexity resulting outputs. example, it now well-appreciated functions multifaceted extend beyond desensitization. Arrestin-coordinated scaffolds downstream give rise distinct ones driven protein. 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Johnson Jimenez-Morales al.Endosomal broadly impacts phosphoproteome.J. 2021; 297100907Google 17Tsvetanova Von Zastrow Spatial encoding specificity 2014; 1061-1065Google Two orthogonal approaches pinpoint functional contributions signaling: acute inhibition photoactivatable ("opto-cyclase") tethered different subcellular sites. With these, found entire gamut changes selectively induced endosome (17Tsvetanova Likewise, GPCR/cAMP reported driver PKA Notably, carefully matching light stimulation conditions yield comparable opto-cyclase experiments, authors alone, rather than total amount messenger, dictates outcomes Similar β2AR, TSHR/Gαs required substrates induction target genes (9Calebiro 11Godbole Hence, this paradigm extends single GPCR, remains determined if principle applies production. Therefore, being strictly membrane-delimited, compartmentalized, functionally differentiate when initiating various 1B). Although referred "location bias" "spatial bias," review uses term encoding" refer phenomenon. To date, reports linked virtually sub-cellular compartments transduced subunits (18Jong Y.I. Harmon within cell.Br. 175: 4026-4035Google Examples organelles harbor include 10Irannejad Scholar), very (19Sposini Jean-Alphonse F.G. Ayoub M.A. Oqua West Lavery al.Integration sorting opposing APPL1 mechanisms.Cell Rep. 21: 2855-2867Google (12Stoeber endoplasmic reticulum (20Jong Intracellular 5 (mGluR5) counterparts.J. 284: 35827-35838Google mitochondrion (21Suofu Y. Li Jia Khattar N.K. al.Dual mitochondria producing melatonin driving block cytochrome c release.Proc. E7997-E8006Google nucleus (22Boivin Lavoie Vaniotis G. Baragli Villeneuve L.R. Ethier N. nuclear membranes adult rat mouse ventricular cardiomyocytes.Cardiovasc. Res. 2006; 71: 69-78Google 23Kumar Jong Activated mGlu5 couples Gq/11 generate inositol 1,4,5-trisphosphate-mediated release.J. 2008; 283: 14072-14083Google ever-growing list comprised couple Gαs, Gαq, Gαi. As below, there ongoing efforts shed consequences GPCRs, based information hand, mechanisms spatial likely diverse. may promote following.•Intracellular proteins: straightforward scenario proteins. endosome, best characterized both Gαs- (e.g., 16Tsvetanova Scholar)) Gαi-coupled delta- mu-opioid Scholar)).•Receptors compartment exhibit kinetics: case certain Vasopressin (V2R) (24Thomsen A.R.B. Cahill Shukla A.K. Dosey A.M. al.GPCR-G protein-β-arrestin super-complex mediates sustained signaling.Cell. 2016; 166: 907-919Google 25Wehbi V.L. Stevenson H.P. Calero Romero Vilardaga Noncanonical arising PTH receptor-arrestin-Gβγ complex.Proc. 110: 1530-1535Google Scholar)), population persistent contrast, Scholar) undergo reversible protein/cAMP endosomes. Whether dynamics encode determined.•Receptors take routes get destination: beta1-adrenergic (β1AR) traffic mechanisms. ligand-dependent followed retrograde Golgi. On β1AR delivered biosynthetic pathway. residence each regulation.•The multiple compartments: Lastly, some organelles. Gαq-coupled mGluR5 elicits ER 26Sergin I. Sequences terminus responsible inner localization.J. 292: 3637-3655Google delta (DOR) mu (MOR), Gαi generated originating unexplored. Recent highlighted endomembrane numerous pathophysiological processes suggested exploited improve therapeutic strategies pathways. We highlight below reference further support (27Jimenez-Vargas N.N. Pattison L.A. Zhao P. Lieu Latorre Jensen D.D. al.Protease-activated receptor-2 pain irritable bowel syndrome.Proc. 115: E7438-e7447Google 28Jensen Halls M.L. Veldhuis N.A. Imlach W.L. al.Neurokinin 1 nociception viable prolonged relief.Sci. Transl. Med. 9https://doi.org/10.1126/scitranslmed.aal3447Google 29Don-Salu-Hewage A.S. Chan S.Y. 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Teng Tonello Retamal al.Mice expressing fluorescent PAR(2) colonic inflammation 119https://doi.org/10.1073/pnas.2112059119Google Work coupled critically shapes physiology across tissues. brain, mediated mGluR5/Gαq It enriched perinuclear region hippocampal neurons, Gαq/Ca2+ long-term depression (LTD) after chemical low-frequency (39Purgert Izumi Zorumski C.F. synaptic plasticity hippocampus.J. 34: 4589-4598Google Similarly, essential another type (MT1R), which Stimulation MT1R cerebrocortical neuroprotective effects blockade release associated caspase important outside central nervous system. kidney cells, V2R leads translocation aquaporin water channels epithelial ion apical membrane, increased sodium permeability (40Feinstein Yui Webber Wehbi King Jr., J.D. al.Noncanonical control vasopressin retromer arrestin.J. 288: 27849-27860Google physiologically advantageous contexts outlined above, implicated drivers disease. selective Golgi-localized myocytes results hypertrophy Gαs-dependent phosphoinositide (15Nash nerve injury spinal dorsal horn increase neuropathic (41Vincent Cornea V.M. Laferriere Mickeviciute al.Intracellular plays pain.Nat. 710604Google implications intriguing possibility therapeutically. One would rely pharmacodynamic properties existing compounds order given compartment. Of specific interest affinity, hydrophobicity, efficacy ligand. Indeed, provided proof-of-principle utility such approaches. Long-acting agonists remain bound Gαs/cAMP elevated serum vitamin D 42White A.D. Pena K.A. Clark L.J. Maria C.S. Liu al.Spatial generation determines biological activation.Sci. Signal. 14eabc5944Google contrasts agonist dissociates rapidly does 43Horwitz Tedesco M.B. Sereika S.M. Syed Garcia-Ocaña Bisello al.Continuous PTHrP infusion causes suppression bone formation discordant 1,25(OH)2 D.J. Bone Miner 1792-1803Google 44Horwitz Hollis Stewart A.F. Direct comparison human hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) calcium, 1,25-dihydroxyvitamin concentrations, fractional excretion healthy volunteers.J. Clin. Endocrinol. Metab. 2003; 88: 1603-1609Google Further, pharmacologic approach relying antagonists hydrophobicity inactivate pathological GPCRs. above attenuated application membrane-permeant antagonist access β1ARs effective preventing compared cannot permeate range efficacies presents yet tool manipulate activity. dopamine, robust internalization, weaker epinephrine, addition targeting itself, entry lumen could manipulated purposes. Catecholamines transported (OCT proteins). Inhibition OCT3 corticosterone abolishes norepinephrine-induced subsequent

Language: Английский

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Beneath the surface: endosomal GPCR signaling

Trends in Biochemical Sciences, Journal Year: 2024, Volume and Issue: 49(6), P. 520 - 531

Published: April 19, 2024

Language: Английский

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Quantitative approaches for studying G protein-coupled receptor signalling and pharmacology

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(1)

Published: Jan. 1, 2025

ABSTRACT G protein-coupled receptor (GPCR) signalling pathways underlie numerous physiological processes, are implicated in many diseases and major targets for therapeutics. There more than 800 GPCRs, which together transduce a vast array of extracellular stimuli into variety intracellular signals via heterotrimeric protein activation multiple downstream effectors. A key challenge cell biology research the pharmaceutical industry is developing tools that enable quantitative investigation GPCR to gain mechanistic insights varied cellular functions pharmacology GPCRs. Recent progress this area has been rapid extensive. In Review, we provide critical overview these new, state-of-the-art approaches investigate pathways. These include novel sensors, Förster or bioluminescence resonance energy transfer assays, libraries tagged proteins transcriptional reporters. improved studies different stages signalling, including activation, second messenger (cAMP Ca2+) β-arrestin recruitment internalisation trafficking

Language: Английский

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cAMP signaling: a remarkably regional affair

Trends in Biochemical Sciences, Journal Year: 2024, Volume and Issue: 49(4), P. 305 - 317

Published: Feb. 2, 2024

Language: Английский

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Development of endosome-related gene signature for the prediction of prognosis and therapeutic response in breast cancer

Medicine, Journal Year: 2025, Volume and Issue: 104(2), P. e41230 - e41230

Published: Jan. 10, 2025

Endosomes play a pivotal role in cellular biology, orchestrating processes such as endocytosis, molecular trafficking, signal transduction, and recycling of materials. This study aims to construct an endosome-related gene (ERG)-derived risk signature for breast cancer prognosis. Transcriptomic clinical data were retrieved from The Cancer Genome Atlas the University California Santa Cruz databases build validate model. A Lasso Cox regression model was employed construction. immune landscape assessed using CIBERSORT ESTIMATE algorithms, while drug sensitivity evaluated via pRRophetic algorithm. Gene set enrichment analysis variation applied evaluate expression patterns. nomogram constructed validated predicting outcomes. ERGs cells tissues further validated. Sixty-one associated with prognosis identified, 23 selected constructing signature. stratified patients into high- low-risk groups, where group exhibited significantly better Notably, younger tended have lower scores compared older ones. enhanced majority drugs tested, accompanied by increased infiltration T M1 macrophages. Additionally, cell cycle pathways suppressed group, whereas antigen binding functions activated. Ultimately, score age identified independent prognostic factors cancer, these incorporated that demonstrated excellent performance assessment. Finally, external cohort dysregulation score-associated tissues. successfully established ERG-derived nomogram, elucidating their potential value prediction evaluation therapeutic response.

Language: Английский

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Integrin signalling in joint development, homeostasis and osteoarthritis

Nature Reviews Rheumatology, Journal Year: 2024, Volume and Issue: 20(8), P. 492 - 509

Published: July 16, 2024

Language: Английский

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SNX27:Retromer:ESCPE-1-mediated early endosomal tubulation impacts cytomegalovirus replication

Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: Sept. 18, 2024

Introduction Cytomegaloviruses (CMVs) extensively reorganize the membrane system of cell and establish a new structure as large nucleus called assembly compartment (AC). Our previous studies on murine CMV (MCMV)-infected fibroblasts indicated that inner part AC contains rearranged early endosomes, recycling endosomal compartments trans-Golgi structures are tubulated, including expansion retention tubular Rab10 elements. An essential process initiates Rab10-associated tubulation is cargo sorting retrieval mediated by SNX27, Retromer, ESCPE-1 (endosomal SNX-BAR complex for promoting exit 1) complexes. Objective The aim this study was to investigate role SNX27:Retromer:ESCPE-1 complexes in biogenesis pre-AC MCMV-infected cells subsequently their secondary envelopment release infectious virions. Results Here we show SNX27:Retromer:ESCPE1-mediated establishment Rab10-decorated subset membranes within pre-AC, function requires an intact F3 subdomain SNX27 FERM domain. Suppression SNX27-mediated functions resulted almost tenfold decrease However, these effects cannot be directly linked contribution SNX27:Retromer:ESCPE-1-dependent envelopment, suppression components, F3-FERM domain, led MCMV protein expression inhibited progression replication cycle. Conclusion This demonstrates novel important associated with control viral expression.

Language: Английский

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Intersection of GPCR trafficking and cAMP signaling at endomembranes

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(4)

Published: March 14, 2025

GPCRs comprise the largest family of signaling receptors and control essentially every physiological process. Many biochemical reactions underlying GPCR are now elucidated to atomic resolution in cell-free preparations, but how elemental organized intact cells remains less clear. Significant progress has been made toward bridging this knowledge gap by leveraging new tools methodologies enabling experimental detection, localization, manipulation defined living cells. Here, we chronicle advances at rapidly moving frontier molecular cell biology, focusing on GPCR-initiated through classical cAMP pathway as an example. We begin with a brief review established concepts. then discuss still-evolving understanding that ligand-induced occurs from endomembranes well plasmalemma, enables flexibly sculpt downstream responses both space time. Finally, note some key limitations present propose promising directions for future investigation.

Language: Английский

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Neurokinin 1 Receptor Endocytosis and Signaling

˜The œReceptors, Journal Year: 2025, Volume and Issue: unknown, P. 325 - 346

Published: Jan. 1, 2025

Language: Английский

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Deciphering complexity of GPCR signaling and modulation: implications and perspectives for drug discovery

Clinical Science, Journal Year: 2025, Volume and Issue: 139(10), P. 463 - 477

Published: May 1, 2025

G protein-coupled receptors (GPCRs) are central to pathophysiological processes and remain prominent targets in drug discovery. Recent advances understanding GPCR signaling modulation, such as biased agonism, dual non-canonical protein signaling, have expanded the therapeutic landscape of these receptors. These understandings led (and leading further) innovative approaches that broaden GPCRs targets, going after better efficacy minimizing adverse effects. However, tachyphylaxis, a rapid decrease receptor responsiveness repeated stimulation, presents significant challenge chronic treatment context. findings from our group revealed tachyphylaxis angiotensin type 1 (AT1) is primarily governed by ligand's dissociation rate (koff), i.e. high residence time, rather than β-arrestin-mediated desensitization, could be expected. This suggests internalized AT1 active when bound ligands with favoring sustained endosomes. Importantly, concept time sheds new light on intracellular phenomena underscores value modulating activity, including development novel cell-permeant antagonists. review discusses critical pharmacological parameters for discovery focused agonists, (i) activation preferential pathways (biased agonism), (ii) internalization/recycling rates, (iii) tachyphylaxis/desensitization, (iv) allosteric modulators, (v) its blockade, emphasizing need strategies extend beyond conventional GPCRs' functional assays. Additionally, this highlights how advancements high-resolution imaging, bioluminescence resonance energy transfer-based biosensors, computational modeling crucial elucidating complex behaviors, particularly mechanisms like interplay compartment-specific signaling. not only pave way therapies strategically leverage or mitigate sustain responsiveness, but enable design drugs targeting strategy enhance minimize insights underscore importance integrating diverse refine GPCR-targeted address unmet medical needs, conditions where activity critical.

Language: Английский

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