53 results found
Gorvin CM, Babinsky VN, Malinauskas T, et al., 2018, A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling, Science Signaling, Vol: 11, ISSN: 1937-9145
The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11and Gi/oto stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-functionCASRmutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+iresponses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSRR680Gin HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+iresponses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11and Gi/oand was mediated instead by a noncanonical pathway involving β-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg680and Glu767, which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg680-Glu767salt bridge in mediating signaling bias.
Gorvin CM, Rogers A, Hastoy B, et al., 2018, AP2? Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity., Cell Rep, Vol: 22, Pages: 1054-1066
Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2 ? subunit (AP2?) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2? mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2? mutations reduced CaSR signaling via G?q/11 and G?i/o pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by G?q/11. Thus, compartmental bias for CaSR-mediated G?q/11 endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling.
Hanyaloglu AC, 2018, Advances in Membrane Trafficking and Endosomal Signaling of G Protein-Coupled Receptors., Int Rev Cell Mol Biol, Vol: 339, Pages: 93-131, ISSN: 1937-6448
The integration of GPCR signaling with membrane trafficking, as a single orchestrated system, is a theme increasingly evident with the growing reports of GPCR endosomal signaling. Once viewed as a mechanism to regulate cell surface heterotrimeric G protein signaling, the endocytic trafficking system is complex, highly compartmentalized, yet deeply interconnected with cell signaling. The organization of receptors into distinct plasma membrane signalosomes, biochemically distinct endosomal populations, endosomal microdomains, and its communication with distinct subcellular organelles such as the Golgi provides multiple unique signaling platforms that are critical for specifying receptor function physiologically and pathophysiologically. In this chapter I discuss our emerging understanding in the endocytic trafficking systems employed by GPCRs and their novel roles in spatial control of signaling. Given the extensive roles that GPCRs play in vivo, these evolving models are starting to provide mechanistic understanding of distinct diseases and provide novel therapeutic avenues that are proving to be viable targets.
Jonas KC, Chen S, Virta M, et al., 2018, Temporal reprogramming of calcium signalling via crosstalk of gonadotrophin receptors that associate as functionally asymmetric heteromers., Sci Rep, Vol: 8
Signal crosstalk between distinct G protein-coupled receptors (GPCRs) is one mechanism that underlies pleiotropic signalling. Such crosstalk is also pertinent for GPCRs activated by gonadotrophic hormones; follicle-stimulating hormone (FSH) and luteinising hormone (LH), with specific relevance to female reproduction. Here, we demonstrate that gonadotrophin receptor crosstalk alters LH-induced Gαq/11-calcium profiles. LH-induced calcium signals in both heterologous and primary human granulosa cells were prolonged by FSHR coexpression via influx of extracellular calcium in a receptor specific manner. LHR/FSHR crosstalk involves Gαq/11 activation as a Gαq/11 inhibitor abolished calcium responses. Interestingly, the enhanced LH-mediated calcium signalling induced by FSHR co-expression was dependent on intracellular calcium store release and involved Gβγ. Biophysical analysis of receptor and Gαq interactions indicated that ligand-dependent association between LHR and Gαq was rearranged in the presence of FSHR, enabling FSHR to closely associate with Gαq following LHR activation. This suggests that crosstalk may occur via close associations as heteromers. Super-resolution imaging revealed that LHR and FSHR formed constitutive heteromers at the plasma membrane. Intriguingly, the ratio of LHR:FSHR in heterotetramers was specifically altered following LH treatment. We propose that functionally significant FSHR/LHR crosstalk reprograms LH-mediated calcium signalling at the interface of receptor-G protein via formation of asymmetric complexes.
Jones B, Buenaventura T, Kanda N, et al., 2018, Targeting GLP-1 receptor trafficking to improve agonist efficacy, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
Owens LA, Abbara A, Lerner A, et al., 2018, The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function, HUMAN REPRODUCTION, Vol: 33, Pages: 292-302, ISSN: 0268-1161
Pyle E, Kalli AC, Amillis S, et al., 2018, Structural Lipids Enable the Formation of Functional Oligomers of the Eukaryotic Purine Symporter UapA, CELL CHEMICAL BIOLOGY, Vol: 25, Pages: 840-+, ISSN: 2451-9448
Schilperoort M, van Dam AD, Hoeke G, et al., 2018, The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat, EMBO Molecular Medicine, Vol: 10, ISSN: 1757-4676
Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT Stimulation of brown adipocytes in vitro with TUG-891 acutely induced O2 consumption, through GPR120-dependent and GPR120-independent mechanisms. TUG-891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG-891 is a promising strategy to increase lipid combustion and reduce obesity.
Sposini S, Hanyaloglu AC, 2018, Evolving View of Membrane Trafficking and Signaling Systems for G Protein-Coupled Receptors., Prog Mol Subcell Biol, Vol: 57, Pages: 273-299, ISSN: 0079-6484
The G protein-coupled receptor (GPCR) superfamily activates complex signal pathways, yet untangling these signaling systems to understand how specificity in receptor signaling pathways is achieved, has been a challenging question. The roles of membrane trafficking in GPCR signal regulation has undergone a recent paradigm shift, from a mechanism that programs the plasma membrane G protein signaling profile to providing distinct signaling platforms critical for specifying receptor function in vivo. In this chapter, we discuss this evolution of our understanding in the endocytic trafficking systems employed by GPCRs, and how such systems play a deeply integrated role with signaling. We describe recent studies that suggest that the endomembrane compartment can provide a mechanism to both specify, and yet also diversify, GPCR signal transduction. These new evolving models could aid mechanistic understanding of complex disease and provide novel therapeutic avenues.
Hanyaloglu AC, Grammatopoulos DK, 2017, Pleiotropic GPCR signaling in health and disease., Mol Cell Endocrinol, Vol: 449, Pages: 1-2
Jonas KC, Hanyaloglu AC, 2017, Impact of G protein-coupled receptor heteromers in endocrine systems, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 449, Pages: 21-27, ISSN: 0303-7207
Sposini S, Hanyaloglu AC, 2017, Spatial encryption of G protein-coupled receptor signaling in endosomes; Mechanisms and applications., Biochem Pharmacol, Vol: 143, Pages: 1-9
Within any cellular signaling system membrane trafficking is a critical mechanism for cells to translate complex networks into specific downstream responses, including the signal pathways activated by the superfamily of G protein-coupled receptors (GPCRs). Classically, membrane trafficking is viewed as a mechanism to regulate ligand sensitivity of a target tissue by controlling the level of surface receptors. Recent studies, however, have not only highlighted that GPCR trafficking is a tightly regulated process critical for spatio-temporal control of signaling, but that heterotrimeric G protein signaling can also be reactivated or continue to signal from distinct endocytic compartments, and even endosomal microdomains. The significance of spatio-temporal control will be discussed, not only with respect to how these novel molecular pathways impact our basic understanding of cellular regulation, but also our view of how aberrant signaling can result in disease. Furthermore, these mechanisms offer the potential application for novel therapeutic strategies to identify GPCR compounds with high specificity in their actions.
Sposini S, Jean-Alphonse FG, Ayoub MA, et al., 2017, Integration of GPCR Signaling and Sorting from Very Early Endosomes via Opposing APPL1 Mechanisms., Cell Rep, Vol: 21, Pages: 2855-2867
Endocytic trafficking is a critical mechanism for cells to decode complex signaling pathways, including those activated by G-protein-coupled receptors (GPCRs). Heterogeneity in the endosomal network enables GPCR activity to be spatially restricted between early endosomes (EEs) and the recently discovered endosomal compartment, the very early endosome (VEE). However, the molecular machinery driving GPCR activity from the VEE is unknown. Using luteinizing hormone receptor (LHR) as a prototype GPCR for this compartment, along with additional VEE-localized GPCRs, we identify a role for the adaptor protein APPL1 in rapid recycling and endosomal cAMP signaling without impacting the EE-localized β2-adrenergic receptor. LHR recycling is driven by receptor-mediated Gαs/cAMP signaling from the VEE and PKA-dependent phosphorylation of APPL1 at serine 410. Receptor/Gαs endosomal signaling is localized to microdomains of heterogeneous VEE populations and regulated by APPL1 phosphorylation. Our study uncovers a highly integrated inter-endosomal communication system enabling cells to tightly regulate spatially encoded signaling.
Babinsky VN, Hannan FM, Gorvin CM, et al., 2016, Allosteric Modulation of the Calcium-sensing Receptor Rectifies Signaling Abnormalities Associated with G-protein α-11 Mutations Causing Hypercalcemic and Hypocalcemic Disorders., J Biol Chem, Vol: 291, Pages: 10876-10885
Germline loss- and gain-of-function mutations of G-protein α-11 (Gα11), which couples the calcium-sensing receptor (CaSR) to intracellular calcium (Ca(2+) i) signaling, lead to familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2), respectively, whereas somatic Gα11 mutations mediate uveal melanoma development by constitutively up-regulating MAPK signaling. Cinacalcet and NPS-2143 are allosteric CaSR activators and inactivators, respectively, that ameliorate signaling disturbances associated with CaSR mutations, but their potential to modulate abnormalities of the downstream Gα11 protein is unknown. This study investigated whether cinacalcet and NPS-2143 may rectify Ca(2+) i alterations associated with FHH2- and ADH2-causing Gα11 mutations, and evaluated the influence of germline gain-of-function Gα11 mutations on MAPK signaling by measuring ERK phosphorylation, and assessed the effect of NPS-2143 on a uveal melanoma Gα11 mutant. WT and mutant Gα11 proteins causing FHH2, ADH2 or uveal melanoma were transfected in CaSR-expressing HEK293 cells, and Ca(2+) i and ERK phosphorylation responses measured by flow-cytometry and Alphascreen immunoassay following exposure to extracellular Ca(2+) (Ca(2+) o) and allosteric modulators. Cinacalcet and NPS-2143 rectified the Ca(2+) i responses of FHH2- and ADH2-associated Gα11 loss- and gain-of-function mutations, respectively. ADH2-causing Gα11 mutations were demonstrated not to be constitutively activating and induced ERK phosphorylation following Ca(2+) o stimulation only. The increased ERK phosphorylation associated with ADH2 and uveal melanoma mutants was rectified by NPS-2143. These findings demonstrate that CaSR-targeted compounds can rectify signaling disturbances caused by germline and somatic Gα11 mutations, which respectively lead to calcium disorders and tumorigenesis; and that ADH2-causing Gα11 mutatio
Jonas KC, Huhtaniemi I, Hanyaloglu AC, 2016, Single-molecule resolution of G protein-coupled receptor (GPCR) complexes, Editors: Shukla, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 55-72, ISBN: 978-0-12-803595-5
Jonas KC, Fanelli F, Huhtaniemi IT, et al., 2015, Single Molecule Analysis of Functionally Asymmetric G Protein-coupled Receptor (GPCR) Oligomers Reveals Diverse Spatial and Structural Assemblies, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 290, Pages: 3875-3892, ISSN: 0021-9258
Psichas A, Sleeth ML, Murphy KG, et al., 2015, The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents, INTERNATIONAL JOURNAL OF OBESITY, Vol: 39, Pages: 424-429, ISSN: 0307-0565
Sposini S, Caltabiano G, Hanyaloglu AC, et al., 2015, Identification of transmembrane domains that regulate spatial arrangements and activity of prokineticin receptor 2 dimers., Mol Cell Endocrinol, Vol: 399, Pages: 362-372
The chemokine prokineticin 2 (PK2) activates its cognate G protein-coupled receptor (GPCR) PKR2 to elicit various downstream signaling pathways involved in diverse biological processes. Many GPCRs undergo dimerization that can modulate a number of functions including membrane delivery and signal transduction. The aim of this study was to elucidate the interface of PKR2 protomers within dimers by analyzing the ability of PKR2 transmembrane (TM) deletion mutants to associate with wild type (WT) PKR2 in yeast using co-immunoprecipitation and mammalian cells using bioluminescence resonance energy transfer. Deletion of TMs 5-7 resulted in a lack of detectable association with WT PKR2, but could associate with a truncated mutant lacking TMs 6-7 (TM1-5). Interestingly, TM1-5 modulated the distance, or organization, between protomers and positively regulated Gαs signaling and surface expression of WT PKR2. We propose that PKR2 protomers form type II dimers involving TMs 4 and 5, with a role for TM5 in modulation of PKR2 function.
West C, Hanyaloglu AC, 2015, Minireview: Spatial Programming of G Protein-Coupled Receptor Activity: Decoding Signaling in Health and Disease., Mol Endocrinol, Vol: 29, Pages: 1095-1106
Probing the multiplicity of hormone signaling via G protein-coupled receptors (GPCRs) has demonstrated the complex signal pathways that underlie the multiple functions these receptors play in vivo. This is highly pertinent for the GPCRs key in reproduction and pregnancy that are exposed to cyclical and dynamic changes in their extracellular milieu. How such functional pleiotropy in GPCR signaling is translated to specific downstream cellular responses, however, is largely unknown. Emerging data strongly support mechanisms for a central role of receptor location in signal regulation via membrane trafficking. In this review, we discuss current progress in our understanding of the role membrane trafficking plays in location control of GPCR signaling, from organized plasma membrane signaling microdomains, potentially provided by both distinct endocytic and exocytic pathways, to more recent evidence for spatial control within the endomembrane system. Application of these emerging mechanisms in their relevance to GPCR activity in physiological and pathophysiological conditions will also be discussed, and in improving therapeutic strategies that exploits these mechanisms in order to program highly regulated and distinct signaling profiles.
Jean-Alphonse F, Bowersox S, Chen S, et al., 2014, Spatially Restricted G Protein-coupled Receptor Activity via Divergent Endocytic Compartments, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 3960-3977, ISSN: 0021-9258
Kandola MK, Sykes L, Lee YS, et al., 2014, EP2 Receptor Activates Dual G Protein Signaling Pathways that Mediate Contrasting Proinflammatory and Relaxatory Responses in Term Pregnant Human Myometrium, ENDOCRINOLOGY, Vol: 155, Pages: 605-617, ISSN: 0013-7227
Kim SH, Blanks A, Thornton S, et al., 2014, Oxytocin Receptor Antagonist, Atosiban, Drives Proinflammatory Effects in Human Amnion Via G(ai) Signaling., REPRODUCTIVE SCIENCES, Vol: 21, Pages: 111A-111A, ISSN: 1933-7191
Nikolopoulou E, Papacleovoulou G, Jean-Alphonse F, et al., 2014, Arachidonic acid-dependent gene regulation during preadipocyte differentiation controls adipocyte potential, JOURNAL OF LIPID RESEARCH, Vol: 55, Pages: 2479-2490, ISSN: 0022-2275
Jonas KC, Rivero-Mueller A, Huhtaniemi IT, et al., 2013, G Protein-Coupled Receptor Transactivation: From Molecules to Mice, RECEPTOR-RECEPTOR INTERACTIONS, Vol: 117, Pages: 433-450, ISSN: 0091-679X
Arulkumaran S, Kandola MK, Hoffman B, et al., 2012, The Roles of Prostaglandin EP 1 and 3 Receptors in the Control of Human Myometrial Contractility, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 97, Pages: 489-498, ISSN: 0021-972X
Arulkumaran S, Kandola MK, Hoffman B, et al., 2012, The Roles of Prostaglandin EP 1 and 3 Receptors in the Control of Human Myometrial Contractility., J Clin Endocrinol Metab, Vol: 97, Pages: 489-498
Al-Sabbagh M, Fusi L, Higham J, et al., 2011, NADPH oxidase-derived reactive oxygen species mediate decidualization of human endometrial stromal cells in response to cyclic AMP signaling., Endocrinology, Vol: 152, Pages: 730-740
Al-Sabbagh M, Fusi L, Higham J, et al., 2011, NADPH Oxidase-Derived Reactive Oxygen Species Mediate Decidualization of Human Endometrial Stromal Cells in Response to Cyclic AMP Signaling, ENDOCRINOLOGY, Vol: 152, Pages: 730-740, ISSN: 0013-7227
Al-Sabbagh M, Fusi L, Higham J, et al., 2011, NADPH Oxidase-Derived Reactive Oxygen Species Mediate Decidualization of Human Endometrial Stromal Cells in Response to Cyclic AMP Signaling, REPRODUCTIVE SCIENCES, Vol: 18, Pages: 162A-162A, ISSN: 1933-7191
Jean-Alphonse F, Hanyaloglu AC, 2011, Regulation of GPCR signal networks via membrane trafficking, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 331, Pages: 205-214, ISSN: 0303-7207
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