About

Nikoleta Georgieva Tsvetanova is an Assistant Professor of Pharmacology and Cancer Biology and an Assistant Professor of Cell Biology at Duke University. She is a member of the Duke Cancer Institute and is involved in research within the Department of Pharmacology and Cancer Biology. Her work focuses on advancing understanding in these fields through her role as primary faculty, contributing to the academic and research community at Duke.

Research topics

• Computational biology
• Biology
• Chemistry
• Genetics
• Biochemistry
• Cell biology
• Economics

Selected publications

• Chemical biology approaches to resolve the subcellular GPCR signaling landscape

  Nature Chemical Biology · 2025-06-02 · 7 citations

  reviewOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• GPCR endocytosis rewires neuronal gene expression and cellular architecture

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-28

  preprintOpen accessSenior authorCorresponding

  In the brain, G protein-coupled receptors (GPCRs) regulate neuronal excitability, synaptic transmission, and behavior by engaging transcriptional and translational programs that produce enduring changes in cellular function and architecture. However, the molecular mechanisms that couple GPCR activation to these adaptations remain poorly understood. Here, we demonstrate that the beta-adrenergic receptor (β2AR), a mediator of noradrenaline in the central nervous system, remodels neuronal morphology through compartmentalized signaling pathways that orchestrate distinct layers of gene regulation. Following stimulation, β2ARs remain active on endosomes, and their intracellular signaling promotes dendritic growth and synapse formation. These structural effects are driven by two coordinated regulatory axes: PKA/CREB-dependent transcription of morphogenesis-related genes and PKA/mTOR-dependent translation of components of the protein synthesis machinery. Altogether, this work defines novel spatial and biochemical principles by which GPCR signaling drives structural reorganization and functional adaptations in neurons.

  PublisherOA PDFDOI

• Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR

  Proceedings of the National Academy of Sciences · 2025-02-18 · 6 citations

  articleOpen accessSenior authorCorresponding

  G protein-coupled receptors (GPCRs) modulate various physiological functions by rewiring cellular gene expression in response to extracellular signals. Control of gene expression by GPCRs has been studied almost exclusively at the transcriptional level, neglecting an extensive amount of regulation that takes place translationally. Hence, little is known about the nature and mechanisms of gene-specific posttranscriptional regulation downstream of receptor activation. Here, we apply an unbiased multiomics approach to delineate an extensive translational regulatory program initiated by the prototypical beta2-adrenergic receptor (β2-AR) and provide mechanistic insights into how these processes are orchestrated. Using ribosome profiling (Ribo-seq), we identify nearly 120 gene targets of adrenergic receptor activity for which expression is exclusively regulated at the level of translation. We next show that all translational changes are induced selectively by endosomal β2-ARs and report that this proceeds through activation of the mammalian target of rapamycin (mTOR) pathway. Specifically, within the set of translational GPCR targets, we find significant enrichment of genes with 5' terminal oligopyrimidine (TOP) motifs, a gene class classically known to be translationally regulated by mTOR. We then demonstrate that endosomal β2-ARs are required for mTOR activation and subsequent mTOR-dependent TOP mRNA translation. This site-selective crosstalk between the pathways is observed in multiple cell models with native β2-ARs, across a range of endogenous and synthetic adrenergic agonists, and for other GPCRs with intracellular activity. Together, this comprehensive analysis of drug-induced translational regulation establishes a critical role for location-biased GPCR signaling in fine-tuning the cellular protein landscape.

  PublisherDOI

• Multiomics approach to interrogate translational regulation to GPCR signaling and its spatial bias

  Journal of Pharmacology and Experimental Therapeutics · 2024-05-13 · 1 citations

  articleSenior author
  PublisherDOI

• Functional diversification of cell signaling by GPCR localization

  Journal of Biological Chemistry · 2024-01-23 · 57 citations

  reviewOpen accessSenior authorCorresponding

  G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and a critical class of regulators of mammalian physiology. Also known as seven transmembrane receptors (7TMs), GPCRs are ubiquitously expressed and versatile, detecting a diverse set of endogenous stimuli, including odorants, neurotransmitters, hormones, peptides, and lipids. Accordingly, GPCRs have emerged as the largest class of drug targets, accounting for upward of 30% of all prescription drugs. The view that ligand-induced GPCR responses originate exclusively from the cell surface has evolved to reflect accumulating evidence that receptors can elicit additional waves of signaling from intracellular compartments. These events in turn shape unique cellular and physiological outcomes. Here, we discuss our current understanding of the roles and regulation of compartmentalized GPCR signaling. G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and a critical class of regulators of mammalian physiology. Also known as seven transmembrane receptors (7TMs), GPCRs are ubiquitously expressed and versatile, detecting a diverse set of endogenous stimuli, including odorants, neurotransmitters, hormones, peptides, and lipids. Accordingly, GPCRs have emerged as the largest class of drug targets, accounting for upward of 30% of all prescription drugs. The view that ligand-induced GPCR responses originate exclusively from the cell surface has evolved to reflect accumulating evidence that receptors can elicit additional waves of signaling from intracellular compartments. These events in turn shape unique cellular and physiological outcomes. Here, we discuss our current understanding of the roles and regulation of compartmentalized GPCR signaling. The classical view had been that GPCR signaling takes place at the cell surface (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: 251-258Google Scholar). The agonist-bound receptor undergoes a conformational change that promotes the activation of the heterotrimeric protein complex, Gαβγ. G proteins are classified into four main families according to their Gα subunit. Gαs and Gαi/o interact with adenylyl cyclase enzymes to stimulate or inhibit the production of cyclic AMP (cAMP), respectively. Gαq activates the mobilization of calcium via phospholipase C (PLC), while Gα12/13 signals vias Rho GTPase stimulation. These second messengers initiate signaling cascades that lead to the regulation of key kinases and transcription factors that coordinate a cellular response. For instance, cAMP activates protein kinase A (PKA). Following ligand binding, the GPCR undergoes post-translational modifications, including phosphorylation of its intracellular loops and/or the C-terminal tail by GPCR kinases (GRKs) (2Gurevich V.V. Gurevich E.V. GPCR signaling regulation: the role of GRKs and arrestins.Front. Pharmacol. 2019; 10: 125Google Scholar). This in turn facilitates the recruitment of β-arrestins one and 2. Classically, the association of arrestins with the receptor was presumed to terminate its signaling in two ways: by sterically hindering interactions with the G protein and by promoting GPCR internalization through the scaffolding of the AP2 adaptor complex and clathrin (2Gurevich V.V. Gurevich E.V. GPCR signaling regulation: the role of GRKs and arrestins.Front. Pharmacol. 2019; 10: 125Google Scholar, 3Lohse M.J. Benovic J.L. Codina J. Caron M.G. Lefkowitz R.J. beta-Arrestin: a protein that regulates beta-adrenergic receptor function.Science. 1990; 248: 1547-1550Google Scholar, 4Cahill 3rd, T.J. Thomsen A.R. Tarrasch J.T. Plouffe B. Nguyen A.H. Yang F. et al.Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 2562-2567Google Scholar). Subsequently, the internalized receptor is sorted and degraded in lysosome or recycled back to the plasma membrane for additional cycles of activation (Fig. 1A). This traditional model has undergone significant revision in the past 2 decades that highlights the immense complexity of the cascades and their resulting signaling outputs. For example, it is now well-appreciated that the functions of arrestins are multifaceted and extend beyond receptor desensitization. Arrestin-coordinated signaling scaffolds downstream of GPCR activation give rise to responses that are distinct from the ones driven by the G protein. While not the subject of the current review, the phenomenon of “arrestin-biased signaling” is of high physiological and pharmacological significance (5Lefkowitz R.J. Shenoy S.K. Transduction of receptor signals by beta-arrestins.Science. 2005; 308: 512-517Google Scholar, 6Shenoy S.K. Lefkowitz R.J. β-Arrestin-mediated receptor trafficking and signal transduction.Trends Pharmacol. Sci. 2011; 32: 521-533Google Scholar). A more recent shift in the classical model involves the discovery that receptors can activate G proteins from intracellular compartments. Early evidence supporting the activation of mammalian G proteins inside the cell emerged from studies of the metabotropic glutamate receptor, mGluR5, and the hormone receptors, TSHR (thyroid stimulating hormone receptor) and PTHR (parathyroid hormone receptor). There, biochemical and pharmacological manipulations were utilized to demonstrate that G protein-dependent production of the second messengers Ca2+ and cAMP is blunted in the absence of activation of the intracellular receptor fractions (7Ferrandon S. Feinstein T.N. Castro M. Wang B. Bouley R. Potts J.T. et al.Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.Nat. Chem. Biol. 2009; 5: 734-742Google Scholar, 8Jong Y.J. Kumar V. Kingston A.E. Romano C. O'Malley K.L. Functional metabotropic glutamate receptors on nuclei from brain and primary cultured striatal neurons. Role of transporters in delivering ligand.J. Biol. Chem. 2005; 280: 30469-30480Google Scholar, 9Calebiro D. Nikolaev V.O. Gagliani M.C. de Filippis T. Dees C. Tacchetti C. et al.Persistent cAMP-signals triggered by internalized G-protein-coupled receptors.PLoS Biol. 2009; 7e1000172Google Scholar). However, these studies relied on indirect and on in vitro methods to examine intracellular GPCR signaling (global endocytic blockade, cell fractionation, temporal correlation between receptor endocytosis and second messenger kinetics). The first direct demonstration of endosomal GPCR and G protein activity emerged from experiments utilizing nanobody-based conformational biosensors in live cells. A study employed two biosensors: Nanobody receptor and a of the G protein activation R. M. J. et biosensors GPCR from Scholar). The with at the cell surface and on ligand-induced receptor activation and internalization R. M. J. et biosensors GPCR from Scholar). The has been to demonstrate the intracellular protein activity for receptors, for GPCRs expressed at A. S. M.J. D. receptors to the signaling and 2017; Scholar, M. D. T. J. et of drug 2018; Scholar, Romano R. The 2 regulates receptor signaling at the Scholar, R. V. D. B. M. et of drug through Chem. Biol. 2017; Scholar, R. receptors stimulate by to 2019; Scholar). are the roles of intracellular G protein This is to evidence that intracellular receptor activity cellular and on receptors in it was that endosomal signaling rise to unique and M. D. et cAMP production the cellular Biol. Chem. Scholar, M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: Scholar). were utilized to the of endosomal pharmacological of endocytosis and cAMP production via a adenylyl cyclase to it was that the of driven by receptor activation is from the M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: Scholar). endosomal was as the primary of protein phosphorylation via M. D. et cAMP production the cellular Biol. Chem. Scholar). by the to cAMP production in their the that the of signaling the of second these unique M. D. et cAMP production the cellular Biol. Chem. Scholar, M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: Scholar). to the intracellular activity from endogenous is for the regulation of and for the of known downstream D. Nikolaev V.O. Gagliani M.C. de Filippis T. Dees C. Tacchetti C. et al.Persistent cAMP-signals triggered by internalized G-protein-coupled receptors.PLoS Biol. 2009; 7e1000172Google Scholar, A. S. M.J. D. receptors to the signaling and 2017; Scholar). beyond a and it to the to all receptors that signal via cAMP plasma receptor signaling is as the cell can the of protein activation responses (Fig. to as or the of GPCR signaling to to have all to GPCR activity via Gα S.K. O'Malley K.L. GPCR from the J. Pharmacol. 2018; Scholar). of that signaling receptors the (7Ferrandon S. Feinstein T.N. Castro M. Wang B. Bouley R. Potts J.T. et al.Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.Nat. Chem. Biol. 2009; 5: 734-742Google Scholar, R. M. J. et biosensors GPCR from S. A. C. S. et of GPCR signaling and from via 2017; M. D. T. J. et of drug 2018; Scholar, Romano R. The 2 regulates receptor signaling at the Scholar, R. V. D. B. M. et of drug through Chem. Biol. 2017; Y.J. Kumar V. O'Malley K.L. metabotropic glutamate receptor activates signaling cascades distinct from cell surface Biol. Chem. 2009; J. J. et role of in and GPCR signaling to Natl. Acad. Sci. U. S. A. 2017; 114: and B. C. A. et beta-adrenergic receptor on in and Scholar, V. Y.J. O'Malley K.L. metabotropic glutamate receptor to proteins to Ca2+ Biol. Chem. Scholar). The of intracellular GPCRs is of receptors that to and we discuss are to on the and regulation of intracellular on the at the functions and of are to of that diverse from intracellular GPCRs the can receptors that to G A for how intracellular receptor activation can lead to involves GPCR signaling via distinct G The one of the signaling to has been to the activation of R. M. J. et biosensors GPCR from Scholar, M. D. et cAMP production the cellular Biol. Chem. and receptors and receptors M. D. T. J. et of drug 2018; that signal from the and to the G protein signaling the of receptors receptor 2 and PTHR Plouffe B. 3rd, T.J. Tarrasch J.T. et G protein Scholar, Feinstein T.N. GPCR signaling from a Natl. Acad. Sci. U. S. A. the endosomal rise to cAMP GPCRs R. M. J. et biosensors GPCR from Scholar, M. D. et cAMP production the cellular Biol. Chem. and G activation on the distinct temporal of the endosomal cAMP signal additional to that signal from the via the G protein trafficking to to their the TSHR and receptor activate Gαs at the A. S. M.J. D. receptors to the signaling and 2017; Scholar, R. V. D. B. M. et of drug through Chem. Biol. 2017; these receptors via distinct The TSHR undergoes internalization into by trafficking to the the the is to the through the it is that the activity and of receptor is subject to unique receptor signals from intracellular receptors stimulate G protein signaling from The GPCR calcium responses from the and Y.J. Kumar V. O'Malley K.L. metabotropic glutamate receptor activates signaling cascades distinct from cell surface Biol. Chem. 2009; Scholar, S.K. Kumar V. O'Malley K.L. the C of the metabotropic glutamate receptor are for membrane Biol. Chem. 2017; Scholar). receptors, and activate signaling from and the M. D. T. J. et of drug 2018; Scholar). The of unique downstream responses that can by the signal from of these is studies have the role of signaling in physiological and and have that of GPCR signaling can to that these of these and additional studies that model T. R. et in signals of Natl. Acad. Sci. U. S. A. 2018; Scholar, T. et receptor signaling in and is a for 2017; Scholar, et receptor undergoes and at the of Scholar, A. B. M. S. et receptor trafficking and signaling, and endosomal to direct 2018; Scholar, F. J. et receptors Scholar, T. C. et signaling of the receptor for Natl. Acad. Sci. U. S. A. 2017; 114: Scholar, D. et and on the membrane and Scholar, A transmembrane intracellular receptor cell 2005; Scholar, J. M.J. R. A. et signaling of receptors is endogenous and for from Natl. Acad. Sci. U. S. A. Scholar, A. S. G protein-coupled receptor in the evidence and roles in physiological and Scholar, S. T. et of in Scholar, R. A. S. R. et that endocytosis and Natl. Acad. Sci. U. S. A. Scholar). on GPCRs to of the main Gα proteins that compartmentalized receptor activity the key are by signaling. was that the metabotropic glutamate receptor is in the of and intracellular is to elicit signaling and and Y.J. Kumar V. O'Malley K.L. can mediate in the Scholar). intracellular signaling is the of for the receptor to of on the membrane of has via of and activation J. J. et role of in and GPCR signaling to Natl. Acad. Sci. U. S. A. 2017; 114: Scholar). protein activation is of the activity of endosomal to the of and to the resulting in and T.N. M.J. et of receptor 2 signaling by and Biol. Chem. Scholar). While in the intracellular GPCRs have been as of For example, of in in through of R. receptors stimulate by to 2019; Scholar). in to in the of and K. A. Kumar A. et a critical role in Scholar). The demonstration that intracellular protein signaling has physiological and has the that phenomenon can on the distinct of in to the receptor at a are the and endocytic of the studies have for the of that to the PTHR internalization into stimulate signaling and elicit calcium and (7Ferrandon S. Feinstein T.N. Castro M. Wang B. Bouley R. Potts J.T. et al.Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.Nat. Chem. Biol. 2009; 5: 734-742Google Scholar, S. et in cAMP responses to receptor Scholar). This with that from the receptor and not endosomal signaling (7Ferrandon S. Feinstein T.N. Castro M. Wang B. Bouley R. Potts J.T. et al.Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.Nat. Chem. Biol. 2009; 5: 734-742Google Scholar, M.J. A. A. et and of and on 2005; Scholar, M.J. A. of of parathyroid on plasma and calcium in Scholar). a on and with distinct has been to the functions of intracellular one example, the in activation in the model of that we discuss can by the of a K. A. Kumar A. et a critical role in Scholar). beta-adrenergic receptor that can the of are at to that the plasma membrane R. receptors stimulate by to 2019; Scholar). The of endocytic of GPCR to compartmentalized receptor For the it was that a ligand that not to signaling to a ligand that receptor endocytosis M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: Scholar). to the receptor the transporters for ligand into the and into the of for are into the cell via transporters of with in cultured activation at the and R. receptors stimulate by to 2019; Scholar). intracellular glutamate via the activity and K. A. Kumar A. et a critical role in Scholar). the GPCR activation to physiological outcomes. we discuss a of intracellular GPCR regulators have been to and of these are of the trafficking evidence the of the endocytic in of the GTPase for membrane of endocytic intracellular and R. A. S. R. et that endocytosis and Natl. Acad. Sci. U. S. A. Scholar). pharmacological of in by the endosomal signal from the receptor J. S. C. et to responses of Scholar). of the of compartmentalized receptor signaling is a key of with the current understanding of how is we on the as it is one of the of intracellular GPCR signaling. is known the regulation of receptor and we additional of the endosomal that are of significance and in studies (Fig. are a class of G protein that mediate the production of cAMP in to G protein and have of distinct with GPCRs on The receptor is with Gαs and on of striatal T. A. M. promotes 2011; Scholar). primary is the main with the complex on and at the D. Nikolaev V.O. Gagliani M.C. de Filippis T. Dees C. Tacchetti C. et al.Persistent cAMP-signals triggered by internalized G-protein-coupled receptors.PLoS Biol. 2009; 7e1000172Google Scholar). to studies have the role of in intracellular GPCR was that is for the of endosomal signaling R. A. et endocytic trafficking of adenylyl cyclase Scholar). The that and Gαs activation promotes the endocytosis of from the plasma membrane into and of cAMP production R. A. et endocytic trafficking of adenylyl cyclase Scholar). While transmembrane one of regulation of signaling, the a role in demonstration was for the hormone receptor signaling via at C. P.A. et cAMP are in G protein-coupled receptor Biol. Scholar). between transmembrane and signaling downstream of intracellular to a recent endosomal receptors transmembrane in turn to calcium and the activation of signaling A. cAMP is for cell Natl. Acad. Sci. U. S. A. Scholar). GPCR signal is by A that cAMP at the cell surface undergoes more to cAMP from the M. D. et cAMP production the cellular Biol. Chem. Scholar). study that activation of receptors with of ligand to the of cAMP signaling are C. K. J. A. et cAMP mediate of GPCR Scholar). of the plasma membrane to the cell at one plasma membrane at cell K. J. Wang D. et and in distinct in Biol. Chem. 2011; Scholar, A. V. M.J. et of with role of compartmentalized Biol. Scholar). can to the cell surface in a was that activation of the to of and to the receptor K.L. et of cyclic AMP to receptors by beta-arrestins.Science. Scholar). This takes place a that is with at the plasma membrane K.L. et of cyclic AMP to receptors by beta-arrestins.Science. Scholar). these the cellular response. A study that of activity signals from the plasma membrane of as signaling M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: Scholar). is to GPCR signaling. to the two key of cAMP arrestins a role in the of the endosomal that elicit cAMP intracellular of the G and Plouffe B. 3rd, T.J. Tarrasch J.T. et G protein Scholar, Feinstein T.N. GPCR signaling from a Natl. Acad. Sci. U. S. A. Scholar). was presumed to terminate G protein signaling, these a the of arrestins to stimulate G protein activation of that was that the endosomal complex a distinct with to the receptor tail to the a unique signaling complex Plouffe B. 3rd, T.J. Tarrasch J.T. et G protein Scholar). β-arrestins are not the family proteins with roles in intracellular GPCR signaling protein with on to receptor R. M. et regulates the endosomal and intracellular signaling of the Biol. Chem. Scholar). a endosomal and the of intracellular cAMP R. M. et regulates the endosomal and intracellular signaling of the Biol. Chem. Scholar). The complex is protein with functions in the regulation of endosomal GPCR and signaling. The complex of protein and their proteins and critical roles in GPCR trafficking and T.N. S. T.J. et the of cAMP by internalized Chem. Biol. 2011; Scholar, B. S. M. and membrane trafficking of Biol. 2011; Scholar). A of studies on the PTHR have a of the role of the in endosomal signaling. was that PTHR signaling to activation of by and association A. T. C. et GPCR signaling by of and Chem. Biol. 10: Scholar). This to terminate the endosomal it was that of the receptor in and more cAMP signaling, while has the T.N. S. T.J. et the of cAMP by internalized Chem. Biol. 2011; Scholar). the of of intracellular PTHR by the is critical for as and T. et PTHR trafficking to for signal regulation in Biol. Scholar). it is that the roles of the complex in compartmentalized GPCR signaling are of significance in the of the a GPCR that signals via cAMP production at of the complex the of intracellular signaling. it was that a the C is for to from into the R. M. trafficking and G protein activation by Biol. Scholar). This in turn rise to endosomal Gαs activation R. M. trafficking and G protein activation by Biol. Scholar). the of and enzymes with the of complexes between the endosomal arrestins and the the of intracellular signaling. However, our of the biochemical at is and many additional to While the to GPCR signaling have on the distinct biochemical of signaling of have been and to of significance in these Early a unique the to the plasma are and their has been as one that mediate the of distinct GPCR A recent study the cell with the of a that complex between a and protein J. GPCR Chem. Biol. Scholar). not the endosomal biochemical complexes for trafficking and signaling J. GPCR Chem. Biol. Scholar). the intracellular of was to inhibit signaling, a for the receptor M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: Scholar, J. GPCR Chem. Biol. Scholar). was that the of the GPCR signal from a on the of with to the of and the of J. GPCR Chem. Biol. Scholar). of the is its Early have a of to while the plasma membrane has a of S. in by of to Biol. Scholar, J. and the of and is the the of endosomal not through regulation of the 2011; Scholar). The of on GPCR activity is to the phenomenon of receptor A of studies are to and the a complex between and GPCR in vitro employed and biochemical to the role of in and that of the from to receptor R. U. et of on for Biol. Chem. Scholar). the in activity and a of conformational change with R. U. et of on for Biol. Chem. Scholar). While it to these to it that in the of the the of the for signaling in the absence of as in the as a to terminate the activity of a the by ligand A. T. C. et GPCR signaling by of and Chem. Biol. 10: Scholar). the to of the of on signaling these The study that regulation is the is and is a of GPCR Natl. Acad. Sci. U. S. A. Scholar). a for and GPCRs in the the activity of protein at and that for receptors, activation is for or high while receptors is a of GPCR Natl. Acad. Sci. U. S. A. Scholar). can G proteins the receptor to on the with receptor 2 to Gαi/o at and Gα12/13 at high the receptor to Gαi/o and at with is a of GPCR Natl. Acad. Sci. U. S. A. Scholar). for ligand and/or is a of GPCR Natl. Acad. Sci. U. S. A. Scholar). is of GPCR signaling, and it is to its in the of the endosomal protein distinct are in unique and is evidence that the can mediate G protein GTPase activity and the recruitment of receptor of the of in mammalian cell that are for and the for the recruitment of was as a Gα protein R. C. C. M. et regulation of G protein-coupled receptor activity by Chem. Biol. Scholar). The significance of on GPCR activity was by in vitro study that the of on A protein complexes et of GPCRs and of 2018; Scholar). was that all receptors to 3rd, T.J. Thomsen A.R. Tarrasch J.T. Plouffe B. Nguyen A.H. Yang F. et al.Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 2562-2567Google Scholar, R.J. Shenoy S.K. Transduction of receptor signals by beta-arrestins.Science. 2005; 308: 512-517Google or a at the plasma membrane V. as membrane Biol. Scholar). This association in turn the receptor and to the G protein and GTPase activity et of GPCRs and of 2018; Scholar). the association of the G proteins as distinct interactions between in the plasma membrane or the and on of the A. R. B. et G protein for G protein-coupled receptors (GPCRs) in live Biol. Chem. 2018; Scholar). These interactions a association between and The were by evidence recruitment of to receptors at the plasma not at the A. S. M. GPCR signal Scholar). the of regulates G protein of G protein to the that association with Gαs by to M.J. S. D. M. membrane regulates receptor to 2019; 10: Scholar). can roles in the recruitment and of GPCR For example, studies have that regulates the and activity of at the plasma membrane K. Lefkowitz R.J. membrane association and activation of the beta-adrenergic receptor kinase coordinate with G and Biol. Chem. Scholar, S.K. J. Benovic J.L. G protein-coupled receptor kinase is a that can by G protein Biol. Chem. Scholar, S.K. J. Benovic J.L. regulation of G protein-coupled receptor kinases 2 and Biol. Chem. Scholar, of on the membrane of the G protein-coupled receptor kinase and the interactions between GPCRs and M. J. A. et of the receptor in complex with Scholar). distinct signaling by unique it to the in vitro with and the for of how shape GPCR to in as by a recent endosomal with recruitment of to D. M. is for GPCR Pharmacol. 2017; Scholar). it is that the of GPCR signaling. While the significance of has not been on known we that the of is in the of The of is to J. The complex of the Biol. Scholar). A of ligand the of a in in the to of the for This in the of that with the as in the experiments are to the of in and intracellular compartments. the unique of signaling are of high and the of to the of additional has the cell evolved for cell surface and intracellular activation of that of receptor signaling to the and of (Fig. intracellular signaling mediate involves the of with at the receptor (Fig. and are endogenous from the is a that to and activates beta-adrenergic receptors with high while is a M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: Scholar, J. C. of to the evidence for conformational Biol. Chem. Scholar). it was that the of and are to cAMP internalization and activation of signaling M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: Scholar). not of GPCR signaling the of from and it was that the is at the cell surface and at the through the M. D. T. J. et of drug 2018; Scholar, A. S. M. GPCR signal Scholar). intracellular are for the of and signaling M. D. et cAMP production the cellular Biol. Chem. Scholar, M. of cyclic AMP signaling by GPCR endocytosis.Nat. Chem. Biol. 10: are from the and a A. S. M. GPCR signal Scholar). downstream are through activation of at the plasma membrane A. S. M. GPCR signal Scholar). are and at the cell while receptor can activate fractions of is to that have not evolved as the of cellular are to endogenous these two we a model of between of the receptor signaling and the of the ligand to direct the GPCR in of a (Fig. GPCR activation as a cellular to receptor activate plasma responses to cellular while activation with high of ligand initiate a second via intracellular signaling to give rise to more of (Fig. it has been that activation of GPCRs in protein post-translational For example, while can by of in activation of the plasma membrane of receptors with a de in of the two receptors et and are by distinct cAMP Chem. Biol. 10: Scholar). of the more to lead to intracellular For ligand-induced internalization for endosomal signaling, to with intracellular as the of receptors is to A for G-protein-coupled receptor J. Scholar). to model through of the of the of a a of a study that of a endosomal receptor from to were with of in the K. of protein kinase C of not from Scholar). endocytosis in a K. of protein kinase C of not from Scholar). more receptors in more The is it to intracellular activation of GPCRs to through the There, of the receptor in the cell a or a ligand transporters in ligand in the of intracellular GPCR signaling are in transporters of transporters Pharmacol. Scholar). and are on and in a activation of intracellular or of or via transporters and Romano R. The 2 regulates receptor signaling at the

  PublisherOA PDFDOI

• Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-18 · 1 citations

  preprintOpen accessSenior authorCorresponding

  G protein-coupled receptors (GPCRs) modulate various physiological functions by re-wiring cellular gene expression in response to extracellular signals. Control of gene expression by GPCRs has been studied almost exclusively at the transcriptional level, neglecting an extensive amount of regulation that takes place translationally. Hence, little is known about the nature and mechanisms of gene-specific post-transcriptional regulation downstream of receptor activation. Here, we apply an unbiased multiomics approach to delineate an extensive translational regulatory program initiated by the prototypical beta2-adrenergic receptor (β2-AR) and provide mechanistic insights into how these processes are orchestrated. Using ribosome profiling (Ribo-seq), we identify nearly 120 novel gene targets of adrenergic receptor activity which expression is exclusively regulated at the level of translation. We next show that all translational changes are induced selectively by endosomal β2-ARs. We further report that this proceeds through activation of the mammalian target of rapamycin (mTOR) pathway. Specifically, within the set of translational GPCR targets we discover significant enrichment of genes with 5' terminal oligopyrimidine (TOP) motifs, a gene class classically known to be translationally regulated by mTOR. We then demonstrate that endosomal β2-ARs are required for mTOR activation and subsequent mTOR-dependent TOP mRNA translation. Together, this comprehensive analysis of drug-induced translational regulation establishes a critical role for location-biased GPCR signaling in fine-tuning the cellular protein landscape.

  PublisherOA PDFDOI

• An engineered trafficking biosensor reveals a role for DNAJC13 in DOR downregulation

  Nature Chemical Biology · 2024-09-02 · 11 citations

  articleOpen access
  PublisherOA PDFDOI

• Author Reply to Peer Reviews of The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction

  2023-04-03

  peer-reviewSenior author
  PublisherDOI

• Multiomics approach to interrogate translational regulation to GPCR signaling and its spatial bias

  Journal of Pharmacology and Experimental Therapeutics · 2023-05-18

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Endosome positioning coordinates spatially selective GPCR signaling

  Nature Chemical Biology · 2023-07-27 · 35 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

Recent grants

• Characterization of Compartmentalized GPCR Signaling in Neurons

  NIH · $1.5M · 2022–2027

• NIH Grant K99MH109633

  NIH · $242k · 2018

• Mechanisms and function of spatially encoded GPCR signaling

  NIH · $403k · 2021–2022

Frequent coauthors

• Mark von Zastrow

  University of California, San Francisco

  32 shared

• Nevan J. Krogan

  Gladstone Institutes

  28 shared

• Jeffrey R. Johnson

  28 shared

• Billy W. Newton

  University of California, San Francisco

  24 shared

• Michelle Trester-Zedlitz

  University of California, San Francisco

  20 shared

• Daniel P. Riordan

  20 shared

• Aparna Sundaram

  University of California System

  16 shared

• David Jimenez‐Morales

  12 shared

Labs

• Research by LabPI