scholarly journals Burnstock and the legacy of the inhibitory junction potential and P2Y1 receptors

Author(s):  
Brian F. King

AbstractThe synaptic event called the inhibitory junction potential (IJP) was arguably one of the more important discoveries made by Burnstock and arguably one of his finer legacies. The discovery of the IJP fundamentally changed how electromechanical coupling was visualised in gastrointestinal smooth muscle. Its discovery also set in motion the search for novel inhibitory neurotransmitters in the enteric nervous system, eventually leading to proposal that ATP or a related nucleotide was a major inhibitory transmitter. The subsequent development of purinergic signalling gave impetus to expanding the classification of surface receptors for extracellular ATP, not only in the GI tract but beyond, and then led to successive phases of medicinal chemistry as the P2 receptor field developed. Ultimately, the discovery of the IJP led to the successful cloning of the first P2Y receptor (chick P2Y1) and expansion of mammalian ATP receptors into two classes: metabotropic P2Y receptors (encompassing P2Y1, P2Y2, P2Y4, P2Y6, P2Y11–14 receptors) and ionotropic P2X receptors (encompassing homomeric P2X1–P2X7 receptors). Here, the causal relationship between the IJP and P2Y1 is explored, setting out the milestones reached and achievements made by Burnstock and his colleagues.

2000 ◽  
Vol 278 (5) ◽  
pp. G725-G733 ◽  
Author(s):  
L. Xue ◽  
G. Farrugia ◽  
J. H. Szurszewski

Intracellular recordings were made from the circular smooth muscle cells of the canine jejunum to study the effect of exogenous ATP and to compare the ATP response to the nonadrenergic, noncholinergic (NANC) inhibitory junction potential (IJP) evoked by electrical field stimulation (EFS). Under NANC conditions, exogenous ATP evoked a transient hyperpolarization (6.5 ± 0.6 mV) and EFS evoked a NANC IJP (17 ± 0.4 mV). ω-Conotoxin GVIA (100 nM) and a low-Ca2+, high-Mg2+ solution abolished the NANC IJP but had no effect on the ATP-evoked hyperpolarization. The ATP-evoked hyperpolarization and the NANC IJP were abolished by apamin (1 μM) and N G-nitro-l-arginine (100 μM). Oxyhemoglobin (5 μM) partially (38.8 ± 5.5%) reduced the amplitude of the NANC IJP but had no effect on the ATP-evoked hyperpolarization. Neither the NANC IJP nor the ATP-evoked hyperpolarization was affected by P2 receptor antagonists or agonists, including suramin, reactive blue 2, 1-( N, O-bis-[5-isoquinolinesulfonyl]- N-methyl-l-tyrosyl)-4-phenylpiperazine, pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid, α,β-methylene ATP, 2-methylthioadenosine 5′-triphosphate tetrasodium salt, and adenosine 5′- O-2-thiodiphosphate. The data suggest that ATP evoked an apamin-sensitive hyperpolarization in circular smooth muscle cells of the canine jejunum via local production of NO in a postsynaptic target cell.


2020 ◽  
Vol 11 (1) ◽  
pp. 8121-8128

P2 receptors have been found in several blood cells and their progenitors. However, most studies lack data about receptor subtypes and of receptors expression time in the process of cell differentiation. The aim of our study was to identify the subtypes of P2Y and P2X receptors on human CD34+ cells, c-kit+ cells, monocytes, lymphocytes of cord and peripheral blood. Expression of P2Y1, P2Y4, and P2Y6 receptors was the uniform in the cord and peripheral blood of all studied cells with the prevalence of monocytes expressing P2Y-receptors (up to 71%). At the same time, a significant difference was found between cells of cord and peripheral blood expressing subtypes of P2X2, P2X3, P2X4, P2X5, P2X6, P2X7 receptors. Cord blood lymphocytes contained a higher percentage of P2X receptors than peripheral blood lymphocytes. Similarly, the percentage of the peripheral blood monocytes, containing P2X receptors was significantly higher than the monocytes of cord blood.


1997 ◽  
Vol 272 (1) ◽  
pp. G77-G83 ◽  
Author(s):  
L. Xue ◽  
H. Suzuki

Electrical responses of gastric smooth muscles produced by transmural nerve stimulation, acetylcholine, norepinephrine, or K-free solution were investigated in streptozotocin-induced diabetic rats, using intracellular microelectrode techniques. In muscles from diabetic rats, 1) the resting membrane potential remained unchanged, 2) slow waves disappeared or were markedly reduced in amplitude, 3) the excitatory junction potential was absent, and in most cases only an inhibitory junction potential of reduced amplitude was elicited, 4) the amplitude of the hyperpolarization generated after superfusion with K-free solution was reduced, 5) the sensitivity of the acetylcholine-induced membrane depolarization was increased, and 6) the norepinephrine-induced hyperpolarization was reduced because of functional loss of alpha- and beta-adrenoceptors. Thus diabetes mellitus caused functional impairment of neuromuscular transmission, reduced the maximum activity of the electrogenic pump, increased the sensitivity of muscarinic receptors, reduced the sensitivity of adrenoceptors, and reduced the myogenic activity in gastric smooth muscles. These alterations in the properties of smooth muscle may be involved in the diabetes-induced gastroparesis.


2013 ◽  
Vol 25 (7) ◽  
pp. 971 ◽  
Author(s):  
F. G. Vázquez-Cuevas ◽  
A. Cruz-Rico ◽  
E. Garay ◽  
A. García-Carrancá ◽  
D. Pérez-Montiel ◽  
...  

Purinergic signalling has been proposed as an intraovarian regulatory mechanism. Of the receptors responsible for purinergic transmission, the P2X7 receptor is an ATP-gated cationic channel that displays a broad spectrum of cellular functions ranging from apoptosis to cell proliferation and tumourigenesis. In the present study, we investigated the functional expression of P2X7 receptors in ovarian surface epithelium (OSE). P2X7 protein was detected in the OSE layer of the mouse, both in situ and in primary cultures. In cultures, 2′(3′)-O-(4-Benzoylbenzoyl)adenosine-5′-triphosphate (BzATP) activation of P2X7 receptors increased [Ca2+]i and induced apoptosis. The functionality of the P2X7 receptor was investigated in situ by intrabursal injection of BzATP on each day of the oestrous cycle and evaluation of apoptosis 24 h using the terminal deoxyribonucleotidyl transferase-mediated dUTP–fluorescein nick end-labelling (TUNEL) assay. Maximum effects of BzATP were observed during pro-oestrus, with the effects being blocked by A438079, a specific P2X7 receptor antagonist. Immunofluorescence staining for P2X7 protein revealed more robust expression during pro-oestrus and in OSE regions behind the antral follicles, strongly supporting the notion that the differences in apoptosis can be explained by increased receptor expression, which is regulated during the oestrous cycle. Finally, P2X7 receptor expression was detected in the OSE layer of human ovaries, with receptor expression maintained in human ovaries diagnosed with cancer, as well as in the human ovarian carcinoma SKOV3 cell line.


1989 ◽  
Vol 173 (2-3) ◽  
pp. 207-209 ◽  
Author(s):  
Adriaan Den Hertog ◽  
Jan Van den Akker ◽  
Adriaan Nelemans

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