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Article ; Online: Signaling diversity of mu- and delta- opioid receptor ligands: Re-evaluating the benefits of β-arrestin/G protein signaling bias.

Pineyro, Graciela / Nagi, Karim

2020 Volume 80, Page(s) 109906

Abstract: Opioid analgesics are elective for treating moderate to severe pain but their use is restricted by severe side effects. Signaling bias has been proposed as a viable means for improving this situation. To exploit this opportunity, continuous efforts are ... ...

Abstract	Opioid analgesics are elective for treating moderate to severe pain but their use is restricted by severe side effects. Signaling bias has been proposed as a viable means for improving this situation. To exploit this opportunity, continuous efforts are devoted to understand how ligand-specific modulations of receptor functions could mediate the different in vivo effects of opioids. Advances in the field have led to the development of biased agonists based on hypotheses that allocated desired and undesired effects to specific signaling pathways. However, the prevalent hypothesis associating β-arrestin to opioid side effects was recently challenged and multiple of the newly developed biased drugs may not display the superior side effects profile that was sought. Moreover, biased agonism at opioid receptors is now known to be time- and cell-dependent, which adds a new layer of complexity for bias estimation. Here, we first review the signaling mechanisms underlying desired and undesired effects of opioids. We then describe biased agonism at opioid receptors and discuss the different perspectives that support the desired and undesired effects of opioids in view of exploiting biased signaling for therapeutic purposes. Finally, we explore how signaling kinetics and cellular background can influence the magnitude and directionality of bias at those receptors.
MeSH term(s)	Analgesics, Opioid/pharmacology ; GTP-Binding Proteins/agonists ; GTP-Binding Proteins/metabolism ; Humans ; Kinetics ; Ligands ; Receptors, Opioid, delta/agonists ; Receptors, Opioid, delta/metabolism ; Receptors, Opioid, mu/agonists ; Receptors, Opioid, mu/metabolism ; Signal Transduction/drug effects ; beta-Arrestins/agonists ; beta-Arrestins/metabolism
Chemical Substances	Analgesics, Opioid ; Ligands ; Receptors, Opioid, delta ; Receptors, Opioid, mu ; beta-Arrestins ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2020-12-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2020.109906
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Zs.A 2579: Show issues

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Article ; Online: Desmontando la masculinidad hegemónica

Carlos Piñeyro

Anthropologica, Vol 40, Iss

una (auto)etnografía del grupo Varones por el Cambio

2023 Volume 49

Abstract: Este texto abordará, desde la etnografía digital y la autoetnografía, la experiencia del colectivo «Varones por el Cambio» - VC, espacio de hombres heterosexuales mayores de cuarenta años surgido en México en 2020, el cual solo ha interactuado de manera ... ...

Abstract	Este texto abordará, desde la etnografía digital y la autoetnografía, la experiencia del colectivo «Varones por el Cambio» - VC, espacio de hombres heterosexuales mayores de cuarenta años surgido en México en 2020, el cual solo ha interactuado de manera virtual usando plataformas como WhatsApp y programas para videoconferencias. Dicho grupo ha cuestionado patrones básicos de la masculinidad hegemónica desde la teoría de los micromachismos de Luis Bonino. Desde este espacio también se han dialogado cuestiones de violencia machista, la cosificación de las mujeres y la importancia de hablar sobre las emociones «negadas» a los varones (miedo, frustración, amor). Así, se verán las posibilidades y los límites de este tipo de procesos desarrollados completamente desde redes sociales, y vividos en primera persona del singular y del plural.
Keywords	Micromachismos ; Masculinidad hegemónica ; Deconstrucción ; Hombres ; Geography. Anthropology. Recreation ; G ; Anthropology ; GN1-890
Language	Spanish
Publishing date	2023-02-01T00:00:00Z
Publisher	Pontificia Universidad Católica del Perú
Document type	Article ; Online
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Article ; Online: Rapid genotyping of porcine reproductive and respiratory syndrome virus (PRRSV) using MinION nanopore sequencing.

Caserta, Leonardo Cardia / Zhang, Jianqiang / Piñeyro, Pablo / Diel, Diego G

PloS one

2023 Volume 18, Issue 5, Page(s) e0282767

Abstract: The global distribution and constant evolution are challenges for the control of porcine reproductive and respiratory syndrome virus (PRRSV), one of the most important viruses affecting swine worldwide. Effective control of PRRSV benefits from genotyping, ...

Abstract	The global distribution and constant evolution are challenges for the control of porcine reproductive and respiratory syndrome virus (PRRSV), one of the most important viruses affecting swine worldwide. Effective control of PRRSV benefits from genotyping, which currently relies on Sanger sequencing. Here we developed and optimized procedures for real-time genotyping and whole genome sequencing of PRRSV directly from clinical samples based on targeted amplicon- and long amplicon tiling sequencing using the MinION Oxford Nanopore platform. Procedures were developed and tested on 154 clinical samples (including lung, serum, oral fluid and processing fluid) with RT-PCR Ct values ranging from 15 to 35. The targeted amplicon sequencing (TAS) approach was developed to obtain sequences of the complete ORF5 (main target gene for PRRSV genotyping) and partial ORF4 and ORF6 sequences of both PRRSV-1 and PRRSV-2 species. After only 5 min of sequencing, PRRSV consensus sequences with identities to reference sequences above 99% were obtained, enabling rapid identification and genotyping of clinical PRRSV samples into lineages 1, 5 and 8. The long amplicon tiling sequencing (LATS) approach targets type 2 PRRSV, the most prevalent viral species in the U.S. and China. Complete PRRSV genomes were obtained within the first hour of sequencing for samples with Ct values below 24.9. Ninety-two whole genome sequences were obtained using the LATS procedure. Fifty out of 60 sera (83.3%) and 18 out of 20 lung samples (90%) had at least 80% of genome covered at a minimum of 20X sequence depth per position. The procedures developed and optimized in this study here are valuable tools with potential for field application during PRRSV elimination programs.
MeSH term(s)	Animals ; Swine ; Genotype ; Nanopore Sequencing ; Porcine respiratory and reproductive syndrome virus ; Chemoradiotherapy ; China
Language	English
Publishing date	2023-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0282767
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Article: A type II cannabis extract and a 1:1 blend of Δ(9)-tetrahydrocannabinol and cannabidiol display distinct antinociceptive profiles and engage different endocannabinoid targets when administered into the subarachnoid space.

Benredjem, Besma / Pineyro, Graciela

Frontiers in pharmacology

2023 Volume 14, Page(s) 1235255

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-09-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1235255
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Article: Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors.

Azzi, Mounia / Charest, Pascale G / Angers, Stéphane / Rousseau, Guy / Kohout, Trudy / Bouvier, Michel / Piñeyro, Graciela

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

2003 Volume 100, Issue 20, Page(s) 11406–11411

Abstract: It is becoming increasingly clear that signaling via G protein-coupled receptors is a diverse ... receptor ligands are commonly classified only according to their ability to modify G protein-dependent ...

Abstract	It is becoming increasingly clear that signaling via G protein-coupled receptors is a diverse phenomenon involving receptor interaction with a variety of signaling partners. Despite this diversity, receptor ligands are commonly classified only according to their ability to modify G protein-dependent signaling. Here we show that beta2AR ligands like ICI118551 and propranolol, which are inverse agonists for Gs-stimulated adenylyl cyclase, induce partial agonist responses for the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) 1/2 thus behaving as dual efficacy ligands. ERK1/2 activation by dual efficacy ligands was not affected by ADP-ribosylation of Galphai and could be observed in S49-cyc- cells lacking Galphas indicating that, unlike the conventional agonist isoproterenol, these drugs induce ERK1/2 activation in a Gs/i-independent manner. In contrast, this activation was inhibited by a dominant negative mutant of beta-arrestin and was abolished in mouse embryonic fibroblasts lacking beta-arrestin 1 and 2. The role of beta-arrestin was further confirmed by showing that transfection of beta-arrestin 2 in these knockout cells restored ICI118551 promoted ERK1/2 activation. ICI118551 and propranolol also promoted beta-arrestin recruitment to the receptor. Taken together, these observations suggest that beta-arrestin recruitment is not an exclusive property of agonists, and that ligands classically classified as inverse agonists rely exclusively on beta-arrestin for their positive signaling activity. This phenomenon is not unique to beta2-adrenergic ligands because SR121463B, an inverse agonist on the V2 vasopressin receptor-stimulated adenylyl cyclase, recruited beta-arrestin and stimulated ERK1/2. These results point to a multistate model of receptor activation in which ligand-specific conformations are capable of differentially activating distinct signaling partners.
MeSH term(s)	Adrenergic beta-Agonists/pharmacology ; Animals ; Arrestins/metabolism ; Cell Line ; GTP-Binding Proteins/metabolism ; Humans ; Mice ; Microscopy, Fluorescence ; Mitogen-Activated Protein Kinases/metabolism ; Propanolamines/pharmacology ; Protein Conformation ; Receptors, Cell Surface/chemistry ; Receptors, Cell Surface/metabolism ; beta-Arrestin 1 ; beta-Arrestin 2 ; beta-Arrestins
Chemical Substances	ARRB1 protein, human ; ARRB2 protein, human ; Adrenergic beta-Agonists ; Arrb1 protein, mouse ; Arrb2 protein, mouse ; Arrestins ; Propanolamines ; Receptors, Cell Surface ; beta-Arrestin 1 ; beta-Arrestin 2 ; beta-Arrestins ; ICI 118551 (46OL1UC10R) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2003-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1936664100
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Article: Editorial: Insights in hyperprolactinemia.

Pineyro, Maria M / Rulli, Susana B / Tamagno, Gianluca

Frontiers in endocrinology

2024 Volume 14, Page(s) 1351471

MeSH term(s)	Humans ; Female ; Hyperprolactinemia/complications ; Prolactin ; Polycystic Ovary Syndrome
Chemical Substances	Prolactin (9002-62-4)
Language	English
Publishing date	2024-01-11
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1351471
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Article ; Online: Five years of porcine circovirus 3: What have we learned about the clinical disease, immune pathogenesis, and diagnosis.

Kroeger, Molly / Temeeyasen, Gun / Piñeyro, Pablo E

Virus research

2022 Volume 314, Page(s) 198764

Abstract: Porcine circovirus type 3 (PCV3) is a non-enveloped, circular, single-stranded DNA virus in the family Circoviridae. This member of the genus Circovirus was initially described as affecting swine in 2016, and new research has provided further insight ... ...

Abstract	Porcine circovirus type 3 (PCV3) is a non-enveloped, circular, single-stranded DNA virus in the family Circoviridae. This member of the genus Circovirus was initially described as affecting swine in 2016, and new research has provided further insight into its structural characteristics, disease presentations, pathogenesis, and immune response following infection. Therefore, this review aims to summarize advances in PCV3-related research about genomic characteristics epidemiology, pathogenesis, immune response, and the development of diagnostics. PCV3 has been detected globally and retrospectively in pigs of all ages and is associated with a range of clinical presentations, including multisystemic inflammatory syndrome, reproductive failure, porcine dermatitis and nephropathy syndrome, and subclinical infection. Experimental studies have successfully reproduced multisystemic inflammation but have not detected clinical disease. These findings, coupled with a large number of reports of coinfections coinciding with PCV3, may suggest that PCV3 infection alone may not be sufficient to cause evidenceable clinical disease. The pathogenesis of PCV3 has not been fully elucidated yet, and while receptors that facilitate cell-viral entry have not been identified, replication has been confirmed in a wide range of cell types, including trophoblasts, myocardiocytes, skin adipocytes, and neurons. PCV3 seems to evade the host immune response as evidenced by persistent viremia 42 days post-infection in experimental and longitudinal field studies despite a strong humoral response. Minimal differences in host cytokine profiles and peripheral cell-mediated responses have been observed, but certainly many questions still surround the mechanisms by which PCV3 evades the immune response. The epidemiology of PCV3 remains unclear, and the exact routes of transmission have not been described; but, PCV3 can be shed in oral fluids, nasal secretions, feces, colostrum, and semen, demonstrating the importance of lateral and vertical transmission. The detection of PCV3 in numerous domesticated and wild animal species, including cattle, dogs, mice, wild boar, chamois, roe deer, ticks, and mosquitoes, suggests the potential for multiple reservoirs and cross-species transmission. Current advances in PCV3 diagnostic tests have the ability to differentiate PCV3 from other PCVs and corroborate its presence within lesions. Given that the economic impact associated with PCV3 infection has not been assessed and the virus has the potential to emerge as a high-prevalence pathogen in the coming years, future research should focus on filling the knowledge gaps identified in this review.
MeSH term(s)	Animals ; Circoviridae Infections/diagnosis ; Circoviridae Infections/epidemiology ; Circoviridae Infections/veterinary ; Circovirus ; Immune System Diseases ; Mice ; Phylogeny ; Retrospective Studies ; Swine ; Swine Diseases/diagnosis ; Swine Diseases/epidemiology ; Swine Diseases/pathology
Language	English
Publishing date	2022-04-01
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2022.198764
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Zs.A 1965: Show issues

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Article: Allosteric effects of G protein overexpression on the binding of beta-adrenergic ligands with distinct inverse efficacies.

Azzi, M / Piñeyro, G / Pontier, S / Parent, S / Ansanay, H / Bouvier, M

Molecular pharmacology

2001 Volume 60, Issue 5, Page(s) 999–1007

Abstract: Allosteric models of G protein-coupled receptors predict that G protein influences the spontaneous ... to preferentially bind to the inactive and uncoupled form(s), changes in the G protein content should influence ... the binding properties of these ligands. To test this hypothesis, we systematically assessed the effect of G ...

Abstract	Allosteric models of G protein-coupled receptors predict that G protein influences the spontaneous isomerization between inactive (R) and active (R) conformations. Since inverse agonists have been proposed to preferentially bind to the inactive and uncoupled form(s), changes in the G protein content should influence the binding properties of these ligands. To test this hypothesis, we systematically assessed the effect of G proteins on the binding of beta(2)-adrenergic ligands with distinct levels of inverse efficacy. Recombinant baculoviruses encoding the human beta(2)-adrenoreceptor (beta(2)AR) were expressed alone or in combination with G protein subunits in Sf9 cells. Coexpression with the G protein alpha s beta 1 gamma 2 did not influence the relative efficacy of the ligands to inhibit the adenylyl cyclase but induced considerable decrease in number of sites detected by [(3)H]ICI 118551, [(3)H]propranolol, and (125)I-cyanopindolol. This loss was proportional to the inverse efficacy of the ligand used as the radiotracer in the assay. The addition of Gpp(NH)p inhibited the effects of G protein overexpression indicating that the G proteins acted allosterically. Consistent with this notion, Western blot analysis revealed that coexpression with the G proteins was not accompanied by a loss of immunoreactive beta(2)AR. Such allosteric effects of the G proteins were also observed in mammalian cells expressing endogenous level of G proteins indicating that the phenomenon is not unique to overexpression systems. Taken together, these results demonstrate that the apparent receptor number detected by radiolabeled inverse agonists is affected by the content in G proteins as a result of their influence on R/R isomerization.
MeSH term(s)	Allosteric Regulation ; Animals ; Baculoviridae/genetics ; Cells, Cultured ; Flow Cytometry ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; Genetic Vectors ; Ligands ; Radioligand Assay ; Receptors, Adrenergic, beta/metabolism ; Spodoptera
Chemical Substances	Ligands ; Receptors, Adrenergic, beta ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2001-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/mol.60.5.999
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Zs.A 525: Show issues

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Article: Bioluminescence resonance energy transfer assays reveal ligand-specific conformational changes within preformed signaling complexes containing delta-opioid receptors and heterotrimeric G proteins.

Audet, Nicolas / Galés, Céline / Archer-Lahlou, Elodie / Vallières, Marc / Schiller, Peter W / Bouvier, Michel / Pineyro, Graciela

The Journal of biological chemistry

2008 Volume 283, Issue 22, Page(s) 15078–15088

Abstract: ... alpha(i1)beta(1)gamma(2) G protein subunits were tagged with Luc or green fluorescent protein to produce ... bioluminescence resonance energy transfer pairs that allowed monitoring DOR-G protein interactions from different ... vantage points. Results showed that DORs and heterotrimeric G proteins formed a constitutive complex ...

Abstract	Heptahelical receptors communicate extracellular information to the cytosolic compartment by binding an extensive variety of ligands. They do so through conformational changes that propagate to intracellular signaling partners as the receptor switches from a resting to an active conformation. This active state has been classically considered unique and responsible for regulation of all signaling pathways controlled by a receptor. However, recent functional studies have challenged this notion and called for a paradigm where receptors would exist in more than one signaling conformation. This study used bioluminescence resonance energy transfer assays in combination with ligands of different functional profiles to provide in vivo physical evidence of conformational diversity of delta-opioid receptors (DORs). DORs and alpha(i1)beta(1)gamma(2) G protein subunits were tagged with Luc or green fluorescent protein to produce bioluminescence resonance energy transfer pairs that allowed monitoring DOR-G protein interactions from different vantage points. Results showed that DORs and heterotrimeric G proteins formed a constitutive complex that underwent structural reorganization upon ligand binding. Conformational rearrangements could not be explained by a two-state model, supporting the idea that DORs adopt ligand-specific conformations. In addition, conformational diversity encoded by the receptor was conveyed to the interaction among heterotrimeric subunits. The existence of multiple active receptor states has implications for the way we conceive specificity of signal transduction.
MeSH term(s)	Fluorescence Resonance Energy Transfer/methods ; Heterotrimeric GTP-Binding Proteins/chemistry ; Heterotrimeric GTP-Binding Proteins/genetics ; Heterotrimeric GTP-Binding Proteins/metabolism ; Humans ; Ligands ; Models, Biological ; Protein Binding/physiology ; Protein Structure, Quaternary/physiology ; Receptors, Opioid, delta/chemistry ; Receptors, Opioid, delta/genetics ; Receptors, Opioid, delta/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Signal Transduction/physiology
Chemical Substances	Ligands ; Receptors, Opioid, delta ; Recombinant Proteins ; Heterotrimeric GTP-Binding Proteins (EC 3.6.5.1)
Language	English
Publishing date	2008-04-01
Publishing country	United States
Document type	Journal Article ; 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.M707941200
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Article: Overoxidation and Oligomerization of

Piñeyro, María Dolores / Chiribao, María Laura / Arias, Diego G / Robello, Carlos / Parodi-Talice, Adriana

Pathogens (Basel, Switzerland)

2023 Volume 12, Issue 10

Abstract: Peroxiredoxins (Prxs) have been shown to be important enzymes for trypanosomatids, counteracting oxidative stress and promoting cell infection and intracellular survival. In this work, we investigate the in vitro sensitivity to overoxidation and the ... ...

Abstract	Peroxiredoxins (Prxs) have been shown to be important enzymes for trypanosomatids, counteracting oxidative stress and promoting cell infection and intracellular survival. In this work, we investigate the in vitro sensitivity to overoxidation and the overoxidation dynamics of
Language	English
Publishing date	2023-10-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens12101273
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