Mechanisms underlying agonist efficacy

2007 ◽  
Vol 35 (4) ◽  
pp. 733-736 ◽  
Author(s):  
P.G. Strange
Keyword(s):  
Time Course ◽  
Binding Assay ◽  
Full Range ◽  
Receptor Activation ◽  
D2 Dopamine Receptor ◽  
Pseudo First Order Reaction ◽  
Rate Determining Step ◽  
Binding Event ◽  
Set Up ◽  
G Protein Coupled

Agonist efficacy is a measure of how well an agonist can stimulate a response system linked to a receptor. Efficacy can be assessed in functional assays and various parameters (Emax, KA/EC50, Emax·KA/EC50) determined. The Emax·KA/EC50 parameter provides a good estimate of efficacy across the full range of efficacy. A convenient assay for the efficacy of agonists for some receptors is provided by the [35S]GTP[S] (guanosine 5′-[γ-[35S]thio]triphosphate)-binding assay. In this assay, the normal GTP-binding event in GPCR (G-protein-coupled receptor) activation is replaced by the binding of the non-hydrolysable analogue [35S]GTP[S]. This assay may be used to profile ligands for their efficacy, and an example here is the D2 dopamine receptor where an efficacy scale has been set up using this assay. The mechanisms underlying the assay have been probed. The time course of [35S]GTP[S] binding follows a pseudo-first-order reaction with [35S]GTP[S] binding reaching equilibrium after approx. 3 h. The [35S]GTP[S]-binding event is the rate-determining step in the assay. Agonists regulate the maximal level of [35S]GTP[S] bound, rather than the rate constant for binding. The [35S]GTP[S]-binding assay therefore determines agonist efficacy on the basis of the amount of [35S]GTP[S] bound rather than the rate of binding.

Effects of D2 dopamine receptor activation in the ventral pallidum on sensory gating and food-motivated learning in control and schizophrenia model (Wisket) rats

2021 ◽  
Vol 400 ◽  
pp. 113047
Author(s):  
László Péczely ◽  
Gabriella Kékesi ◽  
Veronika Kállai ◽  
Tamás Ollmann ◽  
Kristóf László ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Sensory Gating ◽  
Receptor Activation ◽  
Ventral Pallidum ◽  
D2 Dopamine Receptor

scholarly journals Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4312
Author(s):  
Benjamin Lefranc ◽  
Karima Alim ◽  
Cindy Neveu ◽  
Olivier Le Marec ◽  
Christophe Dubessy ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Pharmacological Profile ◽  
Acid Moiety ◽  
Structural Determinants ◽  
Physiological Processes ◽  
Structure Activity ◽  
Peptide Derivatives ◽  
Targeting Peptide ◽  
G Protein Coupled

26RFa is a neuropeptide that activates the rhodopsin-like G protein-coupled receptor QRFPR/GPR103. This peptidergic system is involved in the regulation of a wide array of physiological processes including feeding behavior and glucose homeostasis. Herein, the pharmacological profile of a homogenous library of QRFPR-targeting peptide derivatives was investigated in vitro on human QRFPR-transfected cells with the aim to provide possible insights into the structural determinants of the Phe residues to govern receptor activation. Our work advocates to include in next generations of 26RFa(20–26)-based QRFPR agonists effective substitutions for each Phe unit, i.e., replacement of the Phe22 residue by a constrained 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid moiety, and substitution of both Phe24 and Phe26 by their para-chloro counterpart. Taken as a whole, this study emphasizes that optimized modifications in the C-terminal part of 26RFa are mandatory to design selective and potent peptide agonists for human QRFPR.

scholarly journals A Structural Insight into the Reorientation of Transmembrane Domains 3 and 5 during Family A G Protein-Coupled Receptor Activation

2010 ◽  
Vol 79 (2) ◽  
pp. 262-269 ◽  
Author(s):  
Kamonchanok Sansuk ◽  
Xavier Deupi ◽  
Ivan R. Torrecillas ◽  
Aldo Jongejan ◽  
Saskia Nijmeijer ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Activation ◽  
Transmembrane Domains ◽  
G Protein Coupled Receptor ◽  
Structural Insight ◽  
G Protein Coupled ◽  
Insight Into

scholarly journals Ras-mediated activation of the TORC2–PKB pathway is critical for chemotaxis

2010 ◽  
Vol 190 (2) ◽  
pp. 233-245 ◽  
Author(s):  
Huaqing Cai ◽  
Satarupa Das ◽  
Yoichiro Kamimura ◽  
Yu Long ◽  
Carole A. Parent ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Polymerization ◽  
Time Course ◽  
Specific Inhibitor ◽  
Ras Proteins ◽  
Extracellular Signaling ◽  
Upstream Regulator ◽  
Pkb Phosphorylation ◽  
G Protein Coupled

In chemotactic cells, G protein–coupled receptors activate Ras proteins, but it is unclear how Ras-associated pathways link extracellular signaling to cell migration. We show that, in Dictyostelium discoideum, activated forms of RasC prolong the time course of TORC2 (target of rapamycin [Tor] complex 2)-mediated activation of a myristoylated protein kinase B (PKB; PKBR1) and the phosphorylation of PKB substrates, independently of phosphatidylinositol-(3,4,5)-trisphosphate. Paralleling these changes, the kinetics of chemoattractant-induced adenylyl cyclase activation and actin polymerization are extended, pseudopodial activity is increased and mislocalized, and chemotaxis is impaired. The effects of activated RasC are suppressed by deletion of the TORC2 subunit PiaA. In vitro RasCQ62L-dependent PKB phosphorylation can be rapidly initiated by the addition of a PiaA-associated immunocomplex to membranes of TORC2-deficient cells and blocked by TOR-specific inhibitor PP242. Furthermore, TORC2 binds specifically to the activated form of RasC. These results demonstrate that RasC is an upstream regulator of TORC2 and that the TORC2–PKB signaling mediates effects of activated Ras proteins on the cytoskeleton and cell migration.

User identification across online social networks in practice: Pitfalls and solutions

2016 ◽  
Vol 44 (3) ◽  
pp. 377-391 ◽  
Author(s):  
Azadeh Esfandyari ◽  
Matteo Zignani ◽  
Sabrina Gaito ◽  
Gian Paolo Rossi
Keyword(s):  
Social Networks ◽  
Online Social Networks ◽  
Full Range ◽  
Application Programming Interface ◽  
User Identification ◽  
Application Programming ◽  
Test Sets ◽  
Set Up ◽  
Different Levels ◽  
Programming Interface

To take advantage of the full range of services that online social networks (OSNs) offer, people commonly open several accounts on diverse OSNs where they leave lots of different types of profile information. The integration of these pieces of information from various sources can be achieved by identifying individuals across social networks. In this article, we address the problem of user identification by treating it as a classification task. Relying on common public attributes available through the official application programming interface (API) of social networks, we propose different methods for building negative instances that go beyond usual random selection so as to investigate the effectiveness of each method in training the classifier. Two test sets with different levels of discrimination are set up to evaluate the robustness of our different classifiers. The effectiveness of the approach is measured in real conditions by matching profiles gathered from Google+, Facebook and Twitter.

G-protein-coupled-receptor activation of the smooth muscle calponin gene

2001 ◽  
Vol 357 (2) ◽  
pp. 587-592 ◽  
Author(s):  
Nickolai O. DULIN ◽  
Sergei N. ORLOV ◽  
Chad M. KITCHEN ◽  
Tatyana A. VOYNO-YASENETSKAYA ◽  
Joseph M. MIANO
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
G Protein ◽  
Transcriptional Activation ◽  
Fold Increase ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Mitogen Activated Protein Kinase ◽  
G Protein Coupled

A hallmark of cultured smooth muscle cells (SMCs) is the rapid down-regulation of several lineage-restricted genes that define their in vivo differentiated phenotype. Identifying factors that maintain an SMC differentiated phenotype has important implications in understanding the molecular underpinnings governing SMC differentiation and their subversion to an altered phenotype in various disease settings. Here, we show that several G-protein coupled receptors [α-thrombin, lysophosphatidic acid and angiotensin II (AII)] increase the expression of smooth muscle calponin (SM-Calp) in rat and human SMC. The increase in SM-Calp protein appears to be selective for G-protein-coupled receptors as epidermal growth factor was without effect. Studies using AII showed a 30-fold increase in SM-Calp protein, which was dose- and time-dependent and mediated by the angiotensin receptor-1 (AT1 receptor). The increase in SM-Calp protein with AII was attributable to transcriptional activation of SM-Calp based on increases in steady-state SM-Calp mRNA, increases in SM-Calp promoter activity and complete abrogation of protein induction with actinomycin D. To examine the potential role of extracellular signal-regulated kinase (Erk1/2), protein kinase B, p38 mitogen-activated protein kinase and protein kinase C in AII-induced SM-Calp, inhibitors to each of the signalling pathways were used. None of these signalling molecules appears to be crucial for AII-induced SM-Calp expression, although Erk1/2 may be partially involved. These results identify SM-Calp as a target of AII-mediated signalling, and suggest that the SMC response to AII may incorporate a novel activity of SM-Calp.

The Japanese Occupation of Hainan

1980 ◽  
Vol 14 (1) ◽  
pp. 93-109
Author(s):  
R. T. Phillips
Keyword(s):  
South China ◽  
Full Range ◽  
Japanese Economy ◽  
Chinese Government ◽  
The South ◽  
Sharp Rise ◽  
Japanese Occupation ◽  
Set Up ◽  
Special Sales ◽  
The Tropics

Japanese interest in Hainan stemmed from the desire to emulate the success which they had achieved in Taiwan in an area further south which could offer a full range of tropical products for theuse of the Japanese economy. The naval importance of Hainan was also recognized, because it could dominate the South China Sea from the excellent harbour of San-ya ( Samah) Bay, and there were indications that the island was rich in minerals. The development of official Japanese interest in the island was largely the work of the governor-general's office in Taiwan. Thus in 1918 and 1919 an official from Taiwan called Kaku () was sent to Hainan to observe conditions under the title of special sales office head. In the 1920's the Taiwan government sponsored conferences o the South China Japanese consuls to discuss plans for the area, and in 1935 a conference was held production in the tropics, to coordinate research on the economy, production possibilities and culture of the tropical part of China.Meanwhile Chinese government interest in Hainan began to be aroused in the 1930's, culminating in the visit of T.V. Soong, one of the highest ministers of e Kuintang government, in 1936. Thereafter a rail route a west of the island was surveyed but no furthe progress was made. Private businessmen in the 1930's began to develop rubber plantations to join those set up with overseas Chinese capital in the 1910's,and there was a sharp rise in the area planted to sugar in 1936 as the price of sugar rose. Hence when war broke out between China and Japa,the possibilities for the development were just beginning to be explored.1

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