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Article ; Online: Deciphering the role of glycosaminoglycans in GPCR signaling.

Savransky, Sofya / White, Alex D / Vilardaga, Jean-Pierre

2024 Volume 118, Page(s) 111149

Abstract: G protein-coupled receptors (GPCR) and glycosaminoglycans (GAGs) are two essential components of the cell surface that regulate physiological processes in the body. GPCRs are the most extensive family of transmembrane receptors that control cellular ... ...

Abstract	G protein-coupled receptors (GPCR) and glycosaminoglycans (GAGs) are two essential components of the cell surface that regulate physiological processes in the body. GPCRs are the most extensive family of transmembrane receptors that control cellular responses to extracellular stimuli, while GAGs are polysaccharides that contribute to the function of the extracellular matrix (ECM). Due to their proximity to the plasma membrane, GAGs participate in signal transduction by interacting with various extracellular molecules and cell surface receptors. GAGs can directly interact with certain GPCRs or their ligands (chemokines, peptide hormones and neuropeptides, structural proteins, and enzymes) from the glutamate receptor family, the rhodopsin receptor family, the adhesion receptor family, and the secretin receptor family. These interactions have recently become an emerging topic, providing a new avenue for understanding how GPCR signaling is regulated. This review discusses our current state of knowledge about the role of GAGs in GPCR signaling and function.
MeSH term(s)	Glycosaminoglycans ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/physiology ; Cell Membrane/metabolism ; Rhodopsin/metabolism
Chemical Substances	Glycosaminoglycans ; Receptors, G-Protein-Coupled ; Rhodopsin (9009-81-8)
Language	English
Publishing date	2024-03-22
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2024.111149
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Article ; Online: Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications.

Vilardaga, Jean-Pierre / Clark, Lisa J / White, Alex D / Sutkeviciute, Ieva / Lee, Ji Young / Bahar, Ivet

Endocrine reviews

2022 Volume 44, Issue 3, Page(s) 474–491

Abstract: The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the ...

Abstract	The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the identification of several receptors that engage in sustained signaling responses from subcellular compartments following internalization of the ligand-receptor complex. This phenomenon was initially discovered for the parathyroid hormone (PTH) type 1 receptor (PTH1R), a vital GPCR for maintaining normal calcium and phosphate levels in the body with the paradoxical ability to build or break down bone in response to PTH binding. The diverse biological processes regulated by this receptor are thought to depend on its capacity to mediate diverse modes of cyclic adenosine monophosphate (cAMP) signaling. These include transient signaling at the plasma membrane and sustained signaling from internalized PTH1R within early endosomes mediated by PTH. Here we discuss recent structural, cell signaling, and in vivo studies that unveil potential pharmacological outputs of the spatial versus temporal dimension of PTH1R signaling via cAMP. Notably, the combination of molecular dynamics simulations and elastic network model-based methods revealed how precise modulation of PTH signaling responses is achieved through structure-encoded allosteric coupling within the receptor and between the peptide hormone binding site and the G protein coupling interface. The implications of recent findings are now being explored for addressing key questions on how location bias in receptor signaling contributes to pharmacological functions, and how to drug a difficult target such as the PTH1R toward discovering nonpeptidic small molecule candidates for the treatment of metabolic bone and mineral diseases.
MeSH term(s)	Humans ; Parathyroid Hormone-Related Protein ; Parathyroid Hormone/pharmacology ; Receptor, Parathyroid Hormone, Type 1/metabolism ; Signal Transduction/physiology ; Receptors, G-Protein-Coupled ; Cyclic AMP/metabolism
Chemical Substances	Parathyroid Hormone-Related Protein ; Parathyroid Hormone ; Receptor, Parathyroid Hormone, Type 1 ; Receptors, G-Protein-Coupled ; Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	2022-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603096-8
ISSN	1945-7189 ; 0163-769X
ISSN (online)	1945-7189
ISSN	0163-769X
DOI	10.1210/endrev/bnac032
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Zs.A 1562: Show issues

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Article ; Online: Biased GPCR signaling by the native parathyroid hormone-related protein 1 to 141 relative to its N-terminal fragment 1 to 36.

Peña, Karina A / White, Alex D / Savransky, Sofya / Castillo, Ignacio Portales / Jean-Alphonse, Frédéric G / Gardella, Thomas J / Sutkeviciute, Ieva / Vilardaga, Jean-Pierre

The Journal of biological chemistry

2022 Volume 298, Issue 9, Page(s) 102332

Abstract: The parathyroid hormone (PTH)-related protein (PTHrP) is indispensable for the development of mammary glands, placental calcium ion transport, tooth eruption, bone formation and bone remodeling, and causes hypercalcemia in patients with malignancy. ... ...

Abstract	The parathyroid hormone (PTH)-related protein (PTHrP) is indispensable for the development of mammary glands, placental calcium ion transport, tooth eruption, bone formation and bone remodeling, and causes hypercalcemia in patients with malignancy. Although mature forms of PTHrP in the body consist of splice variants of 139, 141, and 173 amino acids, our current understanding on how endogenous PTHrP transduces signals through its cognate G-protein coupled receptor (GPCR), the PTH type 1 receptor (PTHR), is largely derived from studies done with its N-terminal fragment, PTHrP
MeSH term(s)	Cyclic AMP/metabolism ; Heparin/metabolism ; Humans ; Ligands ; Protein Conformation ; Receptor, Parathyroid Hormone, Type 1/chemistry ; Receptor, Parathyroid Hormone, Type 1/metabolism ; Signal Transduction ; beta-Arrestins/metabolism
Chemical Substances	Ligands ; Receptor, Parathyroid Hormone, Type 1 ; beta-Arrestins ; Heparin (9005-49-6) ; Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	2022-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.102332
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Article ; Online: PTH/PTHrP Receptor Signaling, Allostery, and Structures.

Sutkeviciute, Ieva / Clark, Lisa J / White, Alex D / Gardella, Thomas J / Vilardaga, Jean-Pierre

Trends in endocrinology and metabolism: TEM

2019 Volume 30, Issue 11, Page(s) 860–874

Abstract: The parathyroid hormone (PTH) type 1 receptor (PTHR) is the canonical G protein-coupled receptor (GPCR) for PTH and PTH-related protein (PTHrP) and the key regulator of calcium homeostasis and bone turnover. PTHR function is critical for human health to ... ...

Abstract	The parathyroid hormone (PTH) type 1 receptor (PTHR) is the canonical G protein-coupled receptor (GPCR) for PTH and PTH-related protein (PTHrP) and the key regulator of calcium homeostasis and bone turnover. PTHR function is critical for human health to maintain homeostatic control of ionized serum Ca
MeSH term(s)	Animals ; Endosomes/metabolism ; Humans ; Parathyroid Hormone/metabolism ; Receptor, Parathyroid Hormone, Type 1/chemistry ; Receptor, Parathyroid Hormone, Type 1/metabolism ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/physiology
Chemical Substances	Parathyroid Hormone ; Receptor, Parathyroid Hormone, Type 1 ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2019-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2019.07.011
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Article: Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2

Eastman, Richard T / Rusinova, Radda / Herold, Karl F / Huang, Xi-Ping / Dranchak, Patricia / Voss, Ty C / Rana, Sandeep / Shrimp, Jonathan H / White, Alex D / Hemmings, Hugh C / Roth, Bryan L / Inglese, James / Andersen, Olaf S / Dahlin, Jayme L

bioRxiv : the preprint server for biology

2023

Abstract: Since it was proposed as a potential host-directed antiviral agent for SARS-CoV-2, the antiparasitic drug ivermectin has been investigated thoroughly in clinical trials, which have provided insufficient support for its clinical efficacy. To examine the ... ...

Abstract	Since it was proposed as a potential host-directed antiviral agent for SARS-CoV-2, the antiparasitic drug ivermectin has been investigated thoroughly in clinical trials, which have provided insufficient support for its clinical efficacy. To examine the potential for ivermectin to be repurposed as an antiviral agent, we therefore undertook a series of preclinical studies. Consistent with early reports, ivermectin decreased SARS-CoV-2 viral burden in
Language	English
Publishing date	2023-10-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.23.563088
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Article ; Online: Use of Backbone Modification To Enlarge the Spatiotemporal Diversity of Parathyroid Hormone Receptor-1 Signaling via Biased Agonism.

Liu, Shi / Jean-Alphonse, Frederic G / White, Alex D / Wootten, Denise / Sexton, Patrick M / Gardella, Thomas J / Vilardaga, Jean-Pierre / Gellman, Samuel H

Journal of the American Chemical Society

2019 Volume 141, Issue 37, Page(s) 14486–14490

Abstract: The type-1 parathyroid hormone receptor (PTHR1), which regulates calcium homeostasis and tissue development, has two native agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP). PTH forms a complex with the PTHR1 that is rapidly ... ...

Abstract	The type-1 parathyroid hormone receptor (PTHR1), which regulates calcium homeostasis and tissue development, has two native agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP). PTH forms a complex with the PTHR1 that is rapidly internalized and induces prolonged cAMP production from endosomes. In contrast, PTHrP induces only transient cAMP production, which primarily arises from receptors on the cell surface. We show that backbone modification of PTH(1-34)-NH
MeSH term(s)	Amino Acid Sequence ; Cyclic AMP/biosynthesis ; HEK293 Cells ; Humans ; Parathyroid Hormone-Related Protein/pharmacology ; Receptor, Parathyroid Hormone, Type 1/agonists ; Receptor, Parathyroid Hormone, Type 1/chemistry ; Sequence Homology, Amino Acid ; Signal Transduction
Chemical Substances	PTH1R protein, human ; Parathyroid Hormone-Related Protein ; Receptor, Parathyroid Hormone, Type 1 ; abaloparatide (AVK0I6HY2U) ; Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	2019-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.9b04179
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Article: Use of Backbone Modification To Enlarge the Spatiotemporal Diversity of Parathyroid Hormone Receptor-1 Signaling via Biased Agonism

Liu, Shi / Jean-Alphonse, Frederic G / White, Alex D / Wootten, Denise / Sexton, Patrick M / Gardella, Thomas J / Vilardaga, Jean-Pierre / Gellman, Samuel H

Journal of the American Chemical Society. 2019 Sept. 09, v. 141, no. 37

2019

Abstract	The type-1 parathyroid hormone receptor (PTHR1), which regulates calcium homeostasis and tissue development, has two native agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP). PTH forms a complex with the PTHR1 that is rapidly internalized and induces prolonged cAMP production from endosomes. In contrast, PTHrP induces only transient cAMP production, which primarily arises from receptors on the cell surface. We show that backbone modification of PTH(1–34)-NH2 and abaloparatide (a PTHrP derivative) with a single homologous β-amino acid residue can generate biased agonists that induce prolonged cAMP production from receptors at the cell surface. This unique spatiotemporal profile could be useful for distinguishing effects associated with the duration of cAMP production from effects associated with the site of cAMP production.
Keywords	agonists ; amino acids ; calcium ; cyclic AMP ; endosomes ; homeostasis ; parathyroid hormone ; parathyroid hormone receptors
Language	English
Dates of publication	2019-0909
Size	p. 14486-14490.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.9b04179
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity

bioRxiv

Abstract	Since it was proposed as a potential host-directed antiviral agent for SARS-CoV-2, the antiparasitic drug ivermectin has been investigated thoroughly in clinical trials, which have provided insufficient support for its clinical efficacy. To examine the potential for ivermectin to be repurposed as an antiviral agent, we therefore undertook a series of preclinical studies. Consistent with early reports, ivermectin decreased SARS-CoV-2 viral burden in in vitro models at low micromolar concentrations, five- to ten-fold higher than the reported toxic clinical concentration. At similar concentrations, ivermectin also decreased cell viability and increased biomarkers of cytotoxicity and apoptosis. Further mechanistic and profiling studies revealed that ivermectin nonspecifically perturbs membrane bilayers at the same concentrations where it decreases the SARS-CoV-2 viral burden, resulting in nonspecific modulation of membrane-based targets such as G-protein coupled receptors and ion channels. These results suggest that a primary molecular mechanism for the in vitro antiviral activity of ivermectin may be nonspecific membrane perturbation, indicating that ivermectin is unlikely to be translatable into a safe and effective antiviral agent. These results and experimental workflow provide a useful paradigm for performing preclinical studies on (pandemic-related) drug repurposing candidates.
Keywords	covid19
Language	English
Publishing date	2023-10-24
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.10.23.563088
Database	COVID19

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Article ; Online: Luminescence-activated nucleotide cyclase regulates spatial and temporal cAMP synthesis.

Naim, Nyla / White, Alex D / Reece, Jeff M / Wankhede, Mamta / Zhang, Xuefeng / Vilardaga, Jean-Pierre / Altschuler, Daniel L

The Journal of biological chemistry

2018 Volume 294, Issue 4, Page(s) 1095–1103

Abstract: cAMP is a ubiquitous second messenger that regulates cellular proliferation, differentiation, attachment, migration, and several other processes. It has become increasingly evident that tight regulation of cAMP accumulation and localization confers ... ...

Abstract	cAMP is a ubiquitous second messenger that regulates cellular proliferation, differentiation, attachment, migration, and several other processes. It has become increasingly evident that tight regulation of cAMP accumulation and localization confers divergent yet specific signaling to downstream pathways. Currently, few tools are available that have sufficient spatial and temporal resolution to study location-biased cAMP signaling. Here, we introduce a new fusion protein consisting of a light-activated adenylyl cyclase (bPAC) and luciferase (nLuc). This construct allows dual activation of cAMP production through temporally precise photostimulation or chronic chemical stimulation that can be fine-tuned to mimic physiological levels and duration of cAMP synthesis to trigger downstream events. By targeting this construct to different compartments, we show that cAMP produced in the cytosol and nucleus stimulates proliferation in thyroid cells. The bPAC-nLuc fusion construct adds a new reagent to the available toolkit to study cAMP-regulated processes in living cells.
MeSH term(s)	Adenylyl Cyclases/metabolism ; Animals ; Cell Proliferation ; Cells, Cultured ; Cyclic AMP/biosynthesis ; Enzyme Activation/radiation effects ; HEK293 Cells ; Humans ; Light ; Luciferases/metabolism ; Luminescence ; Rats
Chemical Substances	Cyclic AMP (E0399OZS9N) ; Luciferases (EC 1.13.12.-) ; Adenylyl Cyclases (EC 4.6.1.1)
Language	English
Publishing date	2018-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.AC118.004905
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Article ; Online: G

White, Alex D / Jean-Alphonse, Frederic G / Fang, Fei / Peña, Karina A / Liu, Shi / König, Gabriele M / Inoue, Asuka / Aslanoglou, Despoina / Gellman, Samuel H / Kostenis, Evi / Xiao, Kunhong / Vilardaga, Jean-Pierre

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 13, Page(s) 7455–7460

Abstract: cAMP production upon activation of ... ...

Abstract	cAMP production upon activation of G
MeSH term(s)	Animals ; Arrestins/metabolism ; Cell Membrane/metabolism ; Cyclic AMP/metabolism ; Depsipeptides/pharmacology ; Endosomes/metabolism ; GTP-Binding Protein alpha Subunits, Gq-G11/metabolism ; HEK293 Cells ; Humans ; Mice ; Osteoblasts/metabolism ; Parathyroid Hormone/metabolism ; Phosphatidylinositol 3-Kinase/metabolism ; Primary Cell Culture ; Receptor, Parathyroid Hormone, Type 1/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/physiology ; beta-Arrestins/metabolism
Chemical Substances	Arrestins ; Depsipeptides ; FR900359 ; Parathyroid Hormone ; Receptor, Parathyroid Hormone, Type 1 ; Receptors, G-Protein-Coupled ; beta-Arrestins ; Cyclic AMP (E0399OZS9N) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; GTP-Binding Protein alpha Subunits, Gq-G11 (EC 3.6.5.1)
Language	English
Publishing date	2020-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1918158117
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