scholarly journals A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes

2020 ◽  
Author(s):  
Martin C. Michel ◽  
Martina B. Michel-Reher ◽  
Peter Hein
Keyword(s):  
A Priori ◽  
Drug Effects ◽  
Constitutive Activity ◽  
Inverse Agonism ◽  
Basal Tone ◽  
Product Profile ◽  
A Cell ◽  
Definition Of ◽  
G Protein Coupled ◽  
Chemical Class

As many if not most ligands at G protein-coupled receptor antagonists are inverse agonists, we have systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β3-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β2-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, detection and degree of inverse agonism depends on the cells and tissues under investigation, i.e. is greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, it may differ between parts of a tissue, for instance atria vs. ventricles of the heart, and within a cell type between cellular responses. The basal tone of endogenously expressed receptors often is low, leading to less consistent detection and smaller extent of observed inverse agonism. The extent inverse agonism depends on specific molecular properties of a compound but clusters by chemical class. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development.

scholarly journals A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1923 ◽  
Author(s):  
Martin C. Michel ◽  
Martina B. Michel-Reher ◽  
Peter Hein
Keyword(s):  
A Priori ◽  
Drug Effects ◽  
Constitutive Activity ◽  
Drug Discovery And Development ◽  
Inverse Agonism ◽  
Basal Tone ◽  
Product Profile ◽  
A Cell ◽  
Definition Of ◽  
G Protein Coupled

As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β3-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β2-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, the detection and degree of inverse agonism depend on the cells and tissues under investigation, i.e., they are greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, they may differ between parts of a tissue, for instance, atria vs. ventricles of the heart, and within a cell type, between cellular responses. The basal tone of endogenously expressed receptors is often low, leading to less consistent detection and a lesser extent of observed inverse agonism. Extent inverse agonism depends on specific molecular properties of a compound, but inverse agonism appears to be more common in certain chemical classes. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of the extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development.

Involvement of the constitutive activity of the GHS-R1a (ghrelin G-protein coupled receptor) in the tumorigenesis of somatotroph adenomas

2013 ◽  
Author(s):  
Yves Louis Mear ◽  
Xavier Come Donato ◽  
Marie Pierre Blanchard ◽  
Celine Defilles ◽  
Christophe Lisbonis ◽  
...  
Keyword(s):  
G Protein ◽  
Constitutive Activity ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Aerosol-based antimicrobial photoinactivation in the lungs: an action spectrum study

2021 ◽  
Author(s):  
Chiara Treghini ◽  
Alfonso Dell’Accio ◽  
Franco Fusi ◽  
Giovanni Romano
Keyword(s):  
Light Source ◽  
A Priori ◽  
Action Spectrum ◽  
Multidrug Resistant ◽  
Theoretical Modelling ◽  
Resistant Bacteria ◽  
Lung Infections ◽  
Killing Action ◽  
Definition Of

AbstractChronic lung infections are among the most diffused human infections, being often associated with multidrug-resistant bacteria. In this framework, the European project “Light4Lungs” aims at synthesizing and testing an inhalable light source to control lung infections by antimicrobial photoinactivation (aPDI), addressing endogenous photosensitizers only (porphyrins) in the representative case of S. aureus and P. aeruginosa. In the search for the best emission characteristics for the aerosolized light source, this work defines and calculates the photo-killing action spectrum for lung aPDI in the exemplary case of cystic fibrosis. This was obtained by applying a semi-theoretical modelling with Monte Carlo simulations, according to previously published methodology related to stomach infections and applied to the infected trachea, bronchi, bronchioles and alveoli. In each of these regions, the two low and high oxygen concentration cases were considered to account for the variability of in vivo conditions, together with the presence of endogenous porphyrins and other relevant absorbers/diffusers inside the illuminated biofilm/mucous layer. Furthermore, an a priori method to obtain the “best illumination wavelengths” was defined, starting from maximizing porphyrin and light absorption at any depth. The obtained action spectrum is peaked at 394 nm and mostly follows porphyrin extinction coefficient behavior. This is confirmed by the results from the best illumination wavelengths, which reinforces the robustness of our approach. These results can offer important indications for the synthesis of the aerosolized light source and definition of its most effective emission spectrum, suggesting a flexible platform to be considered in further applications.

scholarly journals Constitutive Activity among Orphan Class-A G Protein Coupled Receptors

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0138463 ◽  
Author(s):  
Adam L. Martin ◽  
Michael A. Steurer ◽  
Robert S. Aronstam
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Constitutive Activity ◽  
Class A ◽  
G Protein Coupled

G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigmThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

2006 ◽  
Vol 84 (3-4) ◽  
pp. 287-297 ◽  
Author(s):  
Fernand Gobeil ◽  
Audrey Fortier ◽  
Tang Zhu ◽  
Michela Bossolasco ◽  
Martin Leduc ◽  
...  
Keyword(s):  
G Protein ◽  
Cell Nucleus ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Cell Metabolism ◽  
Hormone Secretion ◽  
G Protein Coupled Receptors ◽  
A Cell ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

Toward a Functional Definition of the A Priori

1944 ◽  
Vol 41 (6) ◽  
pp. 155
Author(s):  
Arthur Child
Keyword(s):  
A Priori ◽  
Definition Of

Subject of Economic Science

2015 ◽  
pp. 115-120
Author(s):  
D. Egorov
Keyword(s):  
Human Behavior ◽  
Classical Theory ◽  
Adam Smith ◽  
A Priori ◽  
Economic Science ◽  
The Public ◽  
Public Consciousness ◽  
Wealth Of Nations ◽  
Definition Of ◽  
The Relationship

Adam Smith defined economics as “the science of the nature and causes of the wealth of nations” (implicitly appealing – in reference to the “wealth” – to the “value”). Neo-classical theory views it as a science “which studies human behavior in terms of the relationship between the objectives and the limited funds that may have a different use of”. The main reason that turns the neo-classical theory (that serves as the now prevailing economic mainstream) into a tool for manipulation of the public consciousness is the lack of measure (elimination of the “value”). Even though the neo-classical definition of the subject of economics does not contain an explicit rejection of objective measures the reference to “human behavior” inevitably implies methodological subjectivism. This makes it necessary to adopt a principle of equilibrium: if you can not objectively (using a solid measurement) compare different states of the system, we can only postulate the existence of an equilibrium point to which the system tends. Neo-classical postulate of equilibrium can not explain the situation non-equilibrium. As a result, the neo-classical theory fails in matching microeconomics to macroeconomics. Moreover, a denial of the category “value” serves as a theoretical basis and an ideological prerequisite of now flourishing manipulative financial technologies. The author believes in the following two principal definitions: (1) economics is a science that studies the economic system, i.e. a system that creates and recombines value; (2) value is a measure of cost of the object. In our opinion, the value is the information cost measure. It should be added that a disclosure of the nature of this category is not an obligatory prerequisite of its introduction: methodologically, it is quite correct to postulate it a priori. The author concludes that the proposed definitions open the way not only to solve the problem of the measurement in economics, but also to address the issue of harmonizing macro- and microeconomics.

Abstract 256: Readmission Avoidability in Acute Coronary Syndrome Patients

2014 ◽  
Vol 7 (suppl_1) ◽  
Author(s):  
Maria Souphis ◽  
Rachel Sylvester ◽  
Alison Wiles ◽  
Meghana Subramanian ◽  
William Froehlich ◽  
...  
Keyword(s):  
Transitional Care ◽  
Drug Effects ◽  
Care Program ◽  
Readmission Rates ◽  
Coronary Syndrome ◽  
History Of ◽  
Definition Of ◽  
Avoidable Readmission ◽  
Cancer Complications ◽  
Avoidable Readmissions

Background: Readmissions for ACS are common, costly, and potentially preventable. According to Medicare 13.4% of AMI admissions were followed by a rehospitalization within 15 days. A 2007 MedPAC report declared 76% of 30-day readmissions preventable. These rates are used as quality indicators despite lack of consensus on the definition of avoidable and unavoidable readmissions. We sought to define these terms and to analyze the effect of these definitions on 30-day outcomes. Methods: BRIDGE (Bridging the Discharge Gap Effectively) is an NP-led transitional care program for cardiac patients within 14 days of discharge. Retrospective data were abstracted on ACS patients readmitted before their appointments between 2008-2010. All readmissions were characterized as avoidable or unavoidable. Definitions were developed from the literature and in concert with senior cardiologists. Avoidable readmission was defined as being the result of a patient or provider issue that if managed may have prevented the admission. Unavoidable readmissions were defined as a patient in need of acute care. Avoidability status was further divided as related or unrelated to the index diagnosis. Results: Of 1188 BRIDGE referrals 304 (25.6%) experienced ACS events. In comparison to the total ACS population, patients readmitted before their BRIDGE clinic appointment (BC) (n=21, 6.9%) tended to be older, female, and were less likely to have a history of a cath or AMI (Table 1). In this study, 81% (n=17) of early readmissions were deemed unavoidable and most (n=14, 66.7%) were attributed to non-ACS issues or disease progression. These unavoidable readmissions included patients with cancer complications, chest pain, or other non-related diagnoses. Only 19% (n=4) of the readmissions were declared avoidable as a result of patient lack of adherence or provider issues such as adverse drug effects. Conclusion: The majority of early (before BC) readmissions following an index hospitalization for ACS patients referred to BRIDGE were unavoidable and unrelated to ACS. A clear discrepancy is seen between the 76% preventable readmissions in the MedPAC report and the 19% preventable readmissions in this study. Distinctions between unavoidable and avoidable readmissions should inform the utility of 30-day readmission rates as quality metrics.

Selective recruitment of arrestin-3 to clathrin coated pits upon stimulation of G protein-coupled receptors

2000 ◽  
Vol 113 (13) ◽  
pp. 2463-2470 ◽  
Author(s):  
F. Santini ◽  
R.B. Penn ◽  
A.W. Gagnon ◽  
J.L. Benovic ◽  
J.H. Keen
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Coated Pits ◽  
Over Expression ◽  
Physiological Conditions ◽  
A Cell ◽  
G Protein Coupled ◽  
Comparable Magnitude

Non-visual arrestins (arrestin-2 and arrestin-3) play critical roles in the desensitization and internalization of many G protein-coupled receptors. In vitro experiments have shown that both non-visual arrestins bind with high and approximately comparable affinities to activated, phosphorylated forms of receptors. They also exhibit high affinity binding, again of comparable magnitude, to clathrin. Further, agonist-promoted internalization of many receptors has been found to be stimulated by exogenous over-expression of either arrestin2 or arrestin3. The existence of multiple arrestins raises the question whether stimulated receptors are selective for a specific endogenous arrestin under more physiological conditions. Here we address this question in RBL-2H3 cells, a cell line that expresses comparable levels of endogenous arrestin-2 and arrestin-3. When (beta)(2)-adrenergic receptors are stably expressed in these cells the receptors internalize efficiently following agonist stimulation. However, by immunofluorescence microscopy we determine that only arrestin-3, but not arrestin-2, is rapidly recruited to clathrin coated pits upon receptor stimulation. Similarly, in RBL-2H3 cells that stably express physiological levels of m1AChR, the addition of carbachol selectively induces the localization of arrestin-3, but not arrestin-2, to coated pits. Thus, this work demonstrates coupling of G protein-coupled receptors to a specific non-visual arrestin in an in vivo setting.

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