scholarly journals Carbazole and Simplified Derivatives: Novel Tools toward β-Adrenergic Receptors Targeting

2021 ◽  
Vol 11 (12) ◽  
pp. 5486
Author(s):  
Fedora Grande ◽  
Anna De Bartolo ◽  
Maria Antonietta Occhiuzzi ◽  
Anna Caruso ◽  
Carmine Rocca ◽  
...  
Keyword(s):  
Adrenergic Receptors ◽  
Cardiac Activity ◽  
Docking Studies ◽  
G Protein Coupled Receptors ◽  
Carbazole Derivative ◽  
Biological Assays ◽  
H9c2 Cardiomyocytes ◽  
Β Adrenergic Receptors ◽  
G Protein Coupled

β-Adrenergic receptors (β-ARs) are G protein-coupled receptors involved in important physiological and pathological processes related to blood pressure and cardiac activity. The inhibition of cardiac β1-ARs could be beneficial in myocardial hypertrophy, ischemia and failure. Several carbazole-based compounds have been described as promising β-blockers. Herein, we investigate the capability of a carbazole derivative and three simplified indole analogs to interact with the active binding site of β1-AR by molecular docking studies. In the light of the obtained results, our compounds were tested by biological assays in H9c2 cardiomyocytes exposed to isoproterenol (ISO) to confirm their potential as β1-blockers agents, and two of them (8 and 10) showed interesting and promising properties. In particular, these compounds were effective against ISO-dependent in vitro cardiac hypertrophy, even at concentrations lower than the known β-AR antagonist propranolol. Overall, the data suggest that the indole derivatives 8 and 10 could act as potent β1-blockers and, active at low doses, could elicit limited side effects.

scholarly journals Overexpression of Orphan Receptor GPR61 Increases cAMP Levels upon Forskolin Stimulation in HEK293 Cells: in vitro and in silico Validation of 5-(Nonyloxy)Tryptamine as a Low-Affinity Inverse Agonist

Pharmacology ◽  
2019 ◽  
Vol 104 (5-6) ◽  
pp. 377-382
Author(s):  
Pawel Kozielewicz ◽  
Gillian Grafton ◽  
Joanna J. Sajkowska-Kozielewicz ◽  
Nicholas M. Barnes
Keyword(s):  
Docking Studies ◽  
G Protein Coupled Receptors ◽  
Orphan Receptor ◽  
Hek293 Cells ◽  
Intrinsic Activity ◽  
Camp Synthesis ◽  
Class A ◽  
G Protein Coupled ◽  
Camp Levels

GPR61 is an orphan receptor that belongs to Class A of G-protein-coupled receptors. It has been reported that GPR61 has a constitutive activity and couples to Gαs. In the present study, we characterized GPR61 function and ligand binding by experimental and molecular docking studies. We demonstrated that heterologous expression of GPR61 in HEK293 cells enhanced the cAMP synthesis response to forskolin, whereas the basal cAMP synthesis was unaffected. 5-(Nonyloxy)tryptamine inhibited forskolin-stimulated cAMP production in GPR61-expressing HEK293 cells. These studies highlight that the intrinsic activity of this receptor is only measurable following its synergy with Gαs.

scholarly journals Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

2015 ◽  
Vol 88 (3) ◽  
pp. 617-623 ◽  
Author(s):  
Kelly R. Monk ◽  
Jörg Hamann ◽  
Tobias Langenhan ◽  
Saskia Nijmeijer ◽  
Torsten Schöneberg ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
In Vitro Pharmacology ◽  
G Protein Coupled

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.

N-ethyl-N-nitrosourea-based generation of mouse models for mutant G protein-coupled receptors

2006 ◽  
Vol 26 (3) ◽  
pp. 209-217 ◽  
Author(s):  
Johannes Grosse ◽  
Patrick Tarnow ◽  
Holger Römpler ◽  
Boris Schneider ◽  
Reinhard Sedlmeier ◽  
...  
Keyword(s):  
G Protein ◽  
Mouse Models ◽  
Germ Line ◽  
Random Mutagenesis ◽  
G Protein Coupled Receptors ◽  
In Vitro Assays ◽  
Vitro Fertilization ◽  
Type 3 ◽  
G Protein Coupled

Chemical random mutagenesis techniques with the germ line supermutagen N-ethyl- N-nitrosourea (ENU) have been established to provide comprehensive collections of mouse models, which were then mined and analyzed in phenotype-driven studies. Here, we applied ENU mutagenesis in a high-throughput fashion for a gene-driven identification of new mutations. Selected members of the large superfamily of G protein-coupled receptors (GPCR), melanocortin type 3 (Mc3r) and type 4 (Mc4r) receptors, and the orphan chemoattractant receptor GPR33, were used as model targets to prove the feasibility of this approach. Parallel archives of DNA and sperm from mice mutagenized with ENU were screened for mutations in these GPCR, and in vitro assays served as a preselection step before in vitro fertilization was performed to generate the appropriate mouse model. For example, mouse models for inherited obesity were established by selecting fully or partially inactivating mutations in Mc4r. Our technology described herein has the potential to provide mouse models for a GPCR dysfunction of choice within <4 mo and can be extended to other gene classes of interest.

scholarly journals Prospects for use of peptides and their derivatives, structurally corresponding to the G protein-coupled receptors, in medicine

2015 ◽  
Vol 61 (1) ◽  
pp. 19-29 ◽  
Author(s):  
A.O. Shpakov ◽  
E.A. Shpakova
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
High Efficiency ◽  
Clinical Medicine ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Coupled

The regulation of signaling pathways involved in the control of many physiological functions is carried out via the heterotrimeric G protein-coupled receptors (GPCR). The search of effective and selective regulators of GPCR and intracellular signaling cascades coupled with them is one of the important problems of modern fundamental and clinical medicine. Recently data suggest that synthetic peptides and their derivatives, structurally corresponding to the intracellular and transmembrane regions of GPCR, can interact with high efficiency and selectivity with homologous receptors and influence, thus, the functional activity of intracellular signaling cascades and fundamental cellular processes controlled by them. GPCR-peptides are active in both in vitro and in vivo. They regulate hematopoiesis, angiogenesis and cell proliferation, inhibit tumor growth and metastasis, and prevent the inflammatory diseases and septic shock. These data show greatest prospects in the development of the new generations of drugs based on GPCR-derived peptides, capable of regulating the important functions of the organism.

β-Adrenergic receptors, voltage-operated Ca 2+-channels, nuclear triiodothyronine receptors and triiodothyronine concentration in pig myocardium after long-term low-dose amiodarone treatment

1993 ◽  
Vol 129 (4) ◽  
pp. 337-347 ◽  
Author(s):  
Liv Bjørn-Hansen Gøtzsche
Keyword(s):  
Cardiac Surgery ◽  
Nuclear Receptors ◽  
Adrenergic Receptors ◽  
Low Dose ◽  
Binding Capacity ◽  
Drug Concentrations ◽  
Cardiac Strain ◽  
Amiodarone Treatment ◽  
Β Adrenergic Receptors

Similar features during chronic amiodarone treatment and hypothyroidism suggest that amiodarone induces a state of "triiodothyronine (T3)-resistance" or "cardiac hypothyroidism", which may predispose the heart to pump failure under conditions with severe strain, such as recovery after cardiac surgery. Disagreements exist as to how amiodarone, and possibly its main metabolite desethylamiodarone, act upon the various receptor systems in the heart. The aim of the present study was to elucidate whether chronic amiodarone treatment leads to a functional reduction in the number of myocardial nuclear T3 receptors, the myocardial tissue T3 concentration and the number of β-receptors and voltage-operated Ca2+-channels. Finally, special attention was drawn to any changes that could contribute to explain previous reports on reduced haemodynamic reserve in animals exposed to severe cardiac strain, such as cardiac surgery. Pigs (72±2 kg) were assigned randomly to amiodarone treatment (20 mg·kg−1·day−1 for 30±1 days, N = 8); controls received no medical treatment (N = 6). The left ventricle was evaluated for β-adrenergic receptors, voltage-operated Ca2+-channels, T3 nuclear receptors and tissue T3 concentration. Maximum binding capacity for β-receptors and Ca2+-channels was reduced in amiodarone-treated pigs (by 38%, p<0.05, and by 52%, p<0.01) and correlated with tissue drug concentrations for both receptor types (p<0.05). No changes were observed concerning nuclear T3 receptors. In vitro competition studies revealed that amiodarone, but not desethylamiodarone, possessed binding properties to Ca2+-channels, whereas neither of the compounds bound to β-receptors. Desethylamiodarone, but not amiodarone, competitively inhibited T3 binding to its nuclear receptors. Myocardial T3 was undetectable (<0.05 nmol/kg wet wt) in amiodarone-treated pigs. From our observations we suggest that the active metabolite desethylamiodarone, rather than the parent drug, is mainly responsible for the observed local hypothyroid-like effects during amiodarone treatment. The observed changes after treatment with low-dose amiodarone in pigs are likely to have biological implications. Functionally, the changes may imply reduced cardiac reserve during conditions of extraordinary strain.

scholarly journals cAMP levels regulate macrophage alternative activation marker expression

2020 ◽  
pp. 175342592097508
Author(s):  
Swamy Polumuri ◽  
Darren J Perkins ◽  
Stefanie N Vogel
Keyword(s):  
G Protein Coupled Receptors ◽  
Alternative Activation ◽  
Marker Genes ◽  
Marker Expression ◽  
Inflammatory Milieu ◽  
G Protein Coupled ◽  
Camp Levels ◽  
Dependent Pathway

The capacity for macrophages to polarize into distinct functional activation states (e.g., M1, M2) is critical to tune an inflammatory response to the relevant infection or injury. Alternative or M2 polarization of macrophages is most often achieved in vitro in response to IL-4/IL-13 and results in the transcriptional up-regulation of a constellation of characteristic M2 marker genes. In vivo, additional signals from the inflammatory milieu can further increase or decrease M2 marker expression. Particularly, activation of cAMP-generating G protein-coupled receptors is reported to increase M2 markers, but whether this is strictly dependent upon cAMP production is unclear. We report herein that increased cAMP alone can increase IL-4-dependent M2 marker expression through a PKA/C/EBPβ/CREB dependent pathway in murine macrophages.

scholarly journals Specific oxylipins enhance vertebrate hematopoiesis via the receptor GPR132

2018 ◽  
Vol 115 (37) ◽  
pp. 9252-9257 ◽  
Author(s):  
Jamie L. Lahvic ◽  
Michelle Ammerman ◽  
Pulin Li ◽  
Megan C. Blair ◽  
Emma R. Stillman ◽  
...  
Keyword(s):  
Fatty Acids ◽  
G Protein ◽  
Cell Lines ◽  
Saturated Fatty Acids ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Hydroxy Fatty Acids ◽  
High Affinity ◽  
G Protein Coupled

Epoxyeicosatrienoic acids (EETs) are lipid-derived signaling molecules with cardioprotective and vasodilatory actions. We recently showed that 11,12-EET enhances hematopoietic induction and engraftment in mice and zebrafish. EETs are known to signal via G protein-coupled receptors, with evidence supporting the existence of a specific high-affinity receptor. Identification of a hematopoietic-specific EET receptor would enable genetic interrogation of EET signaling pathways, and perhaps clinical use of this molecule. We developed a bioinformatic approach to identify an EET receptor based on the expression of G protein-coupled receptors in cell lines with differential responses to EETs. We found 10 candidate EET receptors that are expressed in three EET-responsive cell lines, but not expressed in an EET-unresponsive line. Of these, only recombinant GPR132 showed EET-responsiveness in vitro, using a luminescence-based β-arrestin recruitment assay. Knockdown of zebrafish gpr132b prevented EET-induced hematopoiesis, and marrow from GPR132 knockout mice showed decreased long-term engraftment capability. In contrast to high-affinity EET receptors, GPR132 is reported to respond to additional hydroxy-fatty acids in vitro, and we found that these same hydroxy-fatty acids enhance hematopoiesis in the zebrafish. We conducted structure–activity relationship analyses using both cell culture and zebrafish assays on diverse medium-chain fatty acids. Certain oxygenated, unsaturated free fatty acids showed high activation of GPR132, whereas unoxygenated or saturated fatty acids had lower activity. Absence of the carbon-1 position carboxylic acid prevented activity, suggesting that this moiety is required for receptor activation. GPR132 responds to a select panel of oxygenated polyunsaturated fatty acids to enhance both embryonic and adult hematopoiesis.

Receiving the Synaptic Message

2017 ◽  
Author(s):  
Peggy Mason
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Adrenergic Receptors ◽  
Acetylcholine Receptors ◽  
G Protein Coupled Receptors ◽  
Metabotropic Receptors ◽  
Second Messenger Systems ◽  
Psychotropic Effects ◽  
G Protein Coupled ◽  
Ionotropic And Metabotropic Receptors

Ionotropic and metabotropic receptors differ in their speed of action, the variety of effects produced after ligand-binding, and in the number of types present in the nervous system. The participation of two ionotropic glutamate receptors in synaptic plasticity is thought to be the cellular basis of learning. The actions of acetylcholine on nicotinic acetylcholine receptors present at the neuromuscular junction are described. The pharmacological profile of the GABAA receptor, central to most neural functions, is introduced. The properties of metabotropic receptors that are coupled to G proteins, termed G protein-coupled receptors (GPCRs), are detailed. Three canonical second-messenger systems through which GPCRs act are briefly described. An introduction to clinical pharmacology focused on how drugs acting on muscarinic and adrenergic receptors produce peripheral and central psychotropic effects is provided. Finally, the role of connexins and gap junctions in myelination and hearing is introduced.

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