scholarly journals 5HT2 receptor activation facilitates P2X receptor mediated excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguus

2008 ◽  
Vol 54 (7) ◽  
pp. 1095-1102 ◽  
Author(s):  
Olga Dergacheva ◽  
Xin Wang ◽  
Harriet Kamendi ◽  
Qi Cheng ◽  
Ramon Manchon Pinol ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Nucleus Ambiguus ◽  
P2x Receptor ◽  
Excitatory Neurotransmission ◽  
5Ht2 Receptor

NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

2019 ◽  
Vol 19 (24) ◽  
pp. 2239-2253 ◽  
Author(s):  
Paul J. Goldsmith
Keyword(s):  
Binding Sites ◽  
Receptor Activation ◽  
Research Area ◽  
Allosteric Modulators ◽  
Nonselective Cation Channels ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Excitatory Neurotransmission ◽  
Psychiatric Conditions ◽  
High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

scholarly journals Modulation of phrenic motoneuron excitability by ATP: consequences for respiratory-related output in vitro

2002 ◽  
Vol 92 (5) ◽  
pp. 1899-1910 ◽  
Author(s):  
Gareth B. Miles ◽  
Marjorie A. Parkis ◽  
Janusz Lipski ◽  
Gregory D. Funk
Keyword(s):  
Pyridoxal Phosphate ◽  
Rapid Onset ◽  
Receptor Activation ◽  
Receptor Expression ◽  
P2x Receptor ◽  
Repetitive Firing ◽  
Burst Amplitude ◽  
Inward Currents ◽  
High Level

On the basis of the high level of P2X receptor expression found in phrenic motoneurons (MN) in rats (Kanjhan et al., J Comp Neurol407: 11–32, 1999) and potentiation of hypoglossal MN inspiratory activity by ATP (Funk et al., J Neurosci 17: 6325–6337, 1997), we tested the hypothesis that ATP receptor activation also modulates phrenic MN activity. This question was examined in rhythmically active brain stem-spinal cord preparations from neonatal rats by monitoring effects of ATP on the activity of spinal C4 nerve roots and phrenic MNs. ATP produced a rapid-onset, dose-dependent, suramin- and pyridoxal-phosphate-6-azophenyl-2′,4′-disulphonic acid 4-sodium-sensitive increase in C4 root tonic discharge and a 22 ± 7% potentiation of inspiratory burst amplitude. This was followed by a slower, 10 ± 5% reduction in burst amplitude. ATPγS, the hydrolysis-resistant analog, evoked only the excitatory response. ATP induced inward currents (57 ± 39 pA) and increased repetitive firing of phrenic MNs. These data, combined with persistence of ATP currents in TTX and immunolabeling for P2X2 receptors in Fluoro-Gold-labeled C4 MNs, implicate postsynaptic P2 receptors in the excitation. Inspiratory synaptic currents, however, were inhibited by ATP. This inhibition differed from that seen in root recordings; it did not follow an excitation, had a faster onset, and was induced by ATPγS. Thus ATP inhibited activity through at least two mechanisms: 1) a rapid P2 receptor-mediated inhibition and 2) a delayed P1 receptor-mediated inhibition associated with hydrolysis of ATP to adenosine. The complex effects of ATP on phrenic MNs highlight the importance of ATP as a modulator of central motor outflows.

Sympathetic and parasympathetic component of bradycardia triggered by stimulation of NTS P2X receptors

2006 ◽  
Vol 290 (2) ◽  
pp. H807-H812 ◽  
Author(s):  
Amy M. Kitchen ◽  
Donal S. O'Leary ◽  
Tadeusz J. Scislo
Keyword(s):  
Low Dose ◽  
Nucleus Tractus Solitarius ◽  
Receptor Activation ◽  
P2x Receptors ◽  
P2x Receptor ◽  
High Dose ◽  
Adrenergic Blockade ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Stimulation Of

We have previously shown that activation of P2X purinoceptors in the subpostremal nucleus tractus solitarius (NTS) produces a rapid bradycardia and hypotension. This bradycardia could occur via sympathetic withdrawal, parasympathetic activation, or a combination of both mechanisms. Thus we investigated the relative roles of parasympathetic activation and sympathetic withdrawal in mediating this bradycardia in chloralose-urethane anesthetized male Sprague-Dawley rats. Microinjections of the selective P2X purinoceptor agonist α,β-methylene ATP (25 pmol/50 nl and 100 pmol/50 nl) were made into the subpostremal NTS in control animals, after atenolol (2 mg/kg iv), a β1-selective antagonist, and after atropine methyl bromide (2 mg/kg iv), a muscarinic receptor antagonist. The bradycardia observed with activation of P2X receptors at the low dose of the agonist is mediated almost entirely by sympathetic withdrawal. After β1-adrenergic blockade, the bradycardia was reduced to just −5.1 ± 0.5 versus −28.8 ± 5.1 beats/min in intact animals. Muscarinic blockade did not produce any significant change in the bradycardic response at the low dose. At the high dose, both β1-adrenergic blockade and muscarinic blockade attenuated the bradycardia similarly, −37.4 ± 6.4 and −40.6 ± 3.7 beats/min, respectively, compared with −88.0 ± 11 beats/min in control animals. Double blockade of both β1-adrenergic and muscarinic receptors virtually abolished the response (−2.5 ± 0.8 beats/min). We conclude that the relative contributions of parasympathetic activation and sympathetic withdrawal are dependent on the extent of P2X receptor activation.

scholarly journals Acute nociception mediated by hindpaw P2X receptor activation in the rat

1997 ◽  
Vol 122 (2) ◽  
pp. 365-371 ◽  
Author(s):  
P. A. Bland-Ward ◽  
P. P. A. Humphrey
Keyword(s):  
Receptor Activation ◽  
P2x Receptor

scholarly journals Novel role for P2X receptor activation in endothelium-dependent vasodilation

2004 ◽  
Vol 143 (5) ◽  
pp. 611-617 ◽  
Author(s):  
Louise S Harrington ◽  
Jane A Mitchell
Keyword(s):  
Receptor Activation ◽  
P2x Receptor

scholarly journals P2X1 receptor activation in HL60 cells

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2659-2664 ◽  
Author(s):  
G Buell ◽  
AD Michel ◽  
C Lewis ◽  
G Collo ◽  
PP Humphrey ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Radioligand Binding ◽  
Atp Release ◽  
Receptor Activation ◽  
P2x Receptor ◽  
Luciferase Assay ◽  
Receptor Protein ◽  
Hl60 Cells ◽  
P2x1 Receptor ◽  
Alpha Beta

Recent cloning of the human P2X1 receptor revealed high levels of its messenger RNA in differentiated promyelocytes (HL60 cells). We found expression of P2X1 receptor protein in HL60 cells by radioligand binding, by immunohistochemistry, using a receptor specific antibody, and by electrophysiology. The currents elicited by adenosine triphosphate (ATP) had the expected properties of P2X1 receptors (rapid desensitization, mimicked by alpha,beta-methylene-ATP). However, these currents were only observed in cells that were pretreated with apyrase, which destroys extracellular ATP, or with suramin, a P2X receptor antagonist. This implies that HL60 cells release ATP, which chronically desensitizes the receptor. ATP release was detected by direct measurement, using the luciferin-luciferase assay. It is concluded that functional P2X1 receptors are present in the membrane of differentiated HL60 cells.

ATP raises [Ca2+]i via different P2-receptor subtypes in freshly isolated and cultured aortic myocytes

1995 ◽  
Vol 269 (1) ◽  
pp. H30-H36 ◽  
Author(s):  
P. Pacaud ◽  
R. Malam-Souley ◽  
G. Loirand ◽  
C. Desgranges
Keyword(s):  
Smooth Muscle ◽  
Cell Cycle Progression ◽  
Cultured Cells ◽  
P2y Receptors ◽  
Receptor Activation ◽  
Culture Conditions ◽  
P2x Receptor ◽  
Receptor Subtypes ◽  
P2y Receptor ◽  
Isolated Cells

In vascular smooth muscle, extracellular ATP induces an increase in intracellular [Ca2+] ([Ca2+]i). Various agonists have been used to characterize P2-purinoceptor subtypes involved in the ATP-induced [Ca2+]i rise, measured by indo 1 fluorescence, in both freshly isolated and cultured rat aortic smooth muscle cells. alpha, beta-Methylene-ATP increased [Ca2+]i via Ca2+ entry through P2x-receptor channels in freshly isolated but not in cultured cells. 2-Methylthio-ATP and ADP failed to release Ca2+ via P2y-receptor activation in freshly isolated cells, whereas such a response was obtained in cultured cells. UTP, by stimulating P2u receptors, released Ca2+ from intracellular stores in both freshly isolated and cultured cells. These results suggest that, in the course of the culture process, P2x-receptor activation-induced responses were lost, whereas P2y-receptor activation-induced [Ca2+]i rise appeared, these two phenomena being independent. Responses to P2x-receptor agonist were lost in all culture conditions, whereas functional P2y receptors appeared only in cells that were stimulated with serum to induce cell cycle progression. The phenotypic modulation of vascular myocytes was therefore associated with a change in the functional P2-purinoceptor subtypes.

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