scholarly journals The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor

2020 ◽  
Vol 22 (1) ◽  
pp. 320
Author(s):  
Jeroen Spanoghe ◽  
Lars E. Larsen ◽  
Erine Craey ◽  
Simona Manzella ◽  
Annelies Van Dycke ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Neuronal Inhibition ◽  
Adenosine A1 ◽  
Mitogen Activated Protein ◽  
A1 Receptor ◽  
G Protein Coupled

Adenosine acts as an endogenous anticonvulsant and seizure terminator in the brain. Many of its anticonvulsive effects are mediated through the activation of the adenosine A1 receptor, a G protein-coupled receptor with a wide array of targets. Activating A1 receptors is an effective approach to suppress seizures. This review gives an overview of the neuronal targets of the adenosine A1 receptor focusing in particular on signaling pathways resulting in neuronal inhibition. These include direct interactions of G protein subunits, the adenyl cyclase pathway and the phospholipase C pathway, which all mediate neuronal hyperpolarization and suppression of synaptic transmission. Additionally, the contribution of the guanyl cyclase and mitogen-activated protein kinase cascades to the seizure-suppressing effects of A1 receptor activation are discussed. This review ends with the cautionary note that chronic activation of the A1 receptor might have detrimental effects, which will need to be avoided when pursuing A1 receptor-based epilepsy therapies.

scholarly journals P109Opposite actions of atrial adenosine A1 receptor on G protein-coupled inwardly-rectifying potassium (GIRK/Kir3.1/3.4) and small Ca2+-activated K+ outward (KCa2/SK) currents

2014 ◽  
Vol 103 (suppl 1) ◽  
pp. S18.5-S19
Author(s):  
B Braganca ◽  
N Oliveira-Monteiro ◽  
S Nogueira-Marques ◽  
F Ferreirinha ◽  
PA Lima ◽  
...  
Keyword(s):  
G Protein ◽  
Adenosine A1 Receptor ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Inwardly Rectifying ◽  
G Protein Coupled

scholarly journals Design, Synthesis and Pharmacological Profile of LUF7746, a Novel Covalent Partial Agonist for the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Xue Yang ◽  
Majlen Dilweg ◽  
Dion Osemwengie ◽  
Lindsey Burggraaff ◽  
Daan van der Es ◽  
...  
Keyword(s):  
G Protein ◽  
Partial Agonist ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Activation Process ◽  
Full Agonist ◽  
Partial Agonists ◽  
Activation Assay ◽  
Adenosine A1 ◽  
A1 Receptor

Partial agonists for G protein-coupled receptors (GPCRs) provide opportunities for novel pharmacotherapies with enhanced on-target safety compared to full agonists. For the human adenosine A1 receptor (hA1AR) this has led to the discovery of capadenoson, which has been in phase IIa clinical trials for heart failure. Accordingly, the design and profiling of novel hA1AR partial agonists has become an important research focus. In this study, we report on LUF7746, a capadenoson derivative bearing an electrophilic fluorosulfonyl moiety, as an irreversibly binding hA1AR modulator. Meanwhile, a nonreactive ligand bearing a methylsulfonyl moiety, LUF7747, was designed as a control probe in our study. In a radioligand binding assay, LUF7746’s apparent affinity increased to nanomolar range with longer pre-incubation time, suggesting an increasing level of covalent binding over time. Moreover, compared to the reference full agonist CPA, LUF7746 was a partial agonist in a hA1AR-mediated G protein activation assay and resistant to blockade with an antagonist/inverse agonist. An in silico structure-based docking study combined with site-directed mutagenesis of the hA1AR demonstrated that amino acid Y2717.36 was the primary anchor point for the covalent interaction. Additionally, a label-free whole-cell assay was set up to identify LUF7746’s irreversible activation of an A1 receptor-mediated cell morphological response. These results led us to conclude that LUF7746 is a novel covalent hA1AR partial agonist and a valuable chemical probe for further mapping the receptor activation process. It may also serve as a prototype for a therapeutic approach in which a covalent partial agonist may cause less on-target side effects, conferring enhanced safety compared to a full agonist.<br>

scholarly journals Design, Synthesis and Pharmacological Profile of LUF7746, a Novel Covalent Partial Agonist for the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Xue Yang ◽  
Majlen Dilweg ◽  
Dion Osemwengie ◽  
Lindsey Burggraaff ◽  
Daan van der Es ◽  
...  
Keyword(s):  
G Protein ◽  
Partial Agonist ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Activation Process ◽  
Full Agonist ◽  
Partial Agonists ◽  
Activation Assay ◽  
Adenosine A1 ◽  
A1 Receptor

Partial agonists for G protein-coupled receptors (GPCRs) provide opportunities for novel pharmacotherapies with enhanced on-target safety compared to full agonists. For the human adenosine A1 receptor (hA1AR) this has led to the discovery of capadenoson, which has been in phase IIa clinical trials for heart failure. Accordingly, the design and profiling of novel hA1AR partial agonists has become an important research focus. In this study, we report on LUF7746, a capadenoson derivative bearing an electrophilic fluorosulfonyl moiety, as an irreversibly binding hA1AR modulator. Meanwhile, a nonreactive ligand bearing a methylsulfonyl moiety, LUF7747, was designed as a control probe in our study. In a radioligand binding assay, LUF7746’s apparent affinity increased to nanomolar range with longer pre-incubation time, suggesting an increasing level of covalent binding over time. Moreover, compared to the reference full agonist CPA, LUF7746 was a partial agonist in a hA1AR-mediated G protein activation assay and resistant to blockade with an antagonist/inverse agonist. An in silico structure-based docking study combined with site-directed mutagenesis of the hA1AR demonstrated that amino acid Y2717.36 was the primary anchor point for the covalent interaction. Additionally, a label-free whole-cell assay was set up to identify LUF7746’s irreversible activation of an A1 receptor-mediated cell morphological response. These results led us to conclude that LUF7746 is a novel covalent hA1AR partial agonist and a valuable chemical probe for further mapping the receptor activation process. It may also serve as a prototype for a therapeutic approach in which a covalent partial agonist may cause less on-target side effects, conferring enhanced safety compared to a full agonist.<br>

Adenosine A1 receptor activation mimics ischemic preconditioning in rat hearts

1997 ◽  
Vol 30 (3) ◽  
pp. 252
Author(s):  
R. de Jonge ◽  
S. Bradamante ◽  
J.W. de Jong
Keyword(s):  
Ischemic Preconditioning ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Rat Hearts ◽  
Adenosine A1 ◽  
A1 Receptor

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.

Regulation of Na(+)-3HCO3- cotransport in rabbit proximal convoluted tubule via adenosine A1 receptor

1993 ◽  
Vol 265 (4) ◽  
pp. F511-F519 ◽  
Author(s):  
M. Takeda ◽  
K. Yoshitomi ◽  
M. Imai
Keyword(s):  
Basolateral Membrane ◽  
Receptor Activation ◽  
Proximal Convoluted Tubule ◽  
Adenosine A1 Receptor ◽  
Intracellular Camp ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Adenosine A1 ◽  
A1 Receptor

We investigated the role of adenosine A1-receptor in the regulation of basolateral Na(+)-3HCO3- cotransporter in the rabbit proximal convoluted tubule (PCT) microperfused in vitro by monitoring basolateral membrane potential and intracellular pH. FK-453, a highly specific A1 antagonist, inhibited basolateral HCO3- conductance in a concentration-dependent manner (10(-10)-10(-5) M). Other A1 antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) at 10(-5) M and theophylline at 10(-3) M, also had similar effects. N6-cyclohexyladenosine (CHA) at 10(-7) M attenuated the effect of low concentration (10(-8) M) of FK-453. Either enhancement of the degradation of adenosine by 0.1 U/ml adenosine deaminase (ADA) or inhibition of adenosine release from the cells by 10(-6) M S-(4-nitrobenzyl)-6-thioinosine (NBTI) mimicked the effects of A1 antagonists. These observations suggest that endogenous adenosine is released from PCT cells and stimulates Na(+)-3HCO3- cotransporter. Both 10(-4) M 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP) and 10(-6) M forskolin also inhibited basolateral HCO3- conductance. Both 10(-6) M FK-453 and 10(-4) M CPT-cAMP decreased the initial rate as well as the magnitude of intracellular acidification induced by reduction of peritubular HCO3- concentration from 25 to 0 mM. Neither 10(-6) M FK-453 nor 10(-7) M CHA changed intracellular Ca2+ concentration as measured by fura-2 fluorescence. These results indicate that adenosine might stimulate HCO3- exit across the basolateral membrane through Na(+)-3HCO3- cotransporter by decreasing intracellular cAMP via A1-receptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)

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