α,β-meATP mimics the effects of the purinergic neurotransmitter in the human and rat colon

Martínez-Cutillas, M.; Gil, Víctor; Gallego, Diana; Mañé, N.; Clavé, Père; Martín, María Teresa; Jiménez, Marcel

doi:10.1016/j.ejphar.2014.06.048

Cited by 14 publications

(18 citation statements)

References 51 publications

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“…The interpretation of such results, however, could be complicated by the facts that multiple purines are substrates for the same enzyme or that enzyme inhibitors may have different potencies for each E-NTPDase. The majority of functional studies does not control for site of action of E-NTPDase inhibitors or for accumulation of specific substrates or products although, at times, the effectiveness of such inhibitors has been questioned due to unanticipated observations (27, 28). …”

Section: Discussionmentioning

confidence: 99%

“…The specific receptor subtype(s) mediating relaxation to exogenous ATP or ADP were not examined in the current study as the responses are likely mediated by several purine receptor subtypes on various cell types that are activated upon bath application of purines. For example, P2Y1 receptors are the predominant receptors mediating the inhibitory responses to purine neurotransmitters in the colon (40, 41); however, the relaxation responses to either ATP or ADP in the colon were not inhibited by P2Y1 receptor antagonists or in colons isolated from P2ry1 −/− mice (28, 40, 41), suggesting that receptors in addition to the P2Y1 receptors were responsible for the relaxation responses to ATP or ADP. Further studies would be required to identify the underlying mechanisms of the relaxation responses to extracellular purines in the murine colon.…”

Section: Discussionmentioning

confidence: 99%

“…Since ATP and ADP may activate different receptor sites or target cells the interpretation of the results may be different. This phenomenon may not be restricted to the mouse colon as studies showed that effects in the presence of ARL-67156 may not always be explained with accumulation of ATP (27, 28) and ARL-67156 caused accumulation of ADP (not ATP) in the mouse brain (26). …”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is possible that effects that are obtained in the presence of ARL-67156 are mediated by ADP and not by ATP. The effectiveness of ARL-67156 as an inhibitor of the enteric purinergic neurotransmitter degradation (27) or of ATP catabolism in the colon (28) has been questioned, but direct validation of ARL-67156 effects on ATP or ADP degradation in the GI tract has not been done previously.…”

Section: Introductionmentioning

confidence: 99%

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A commonly used ecto‐ATPase inhibitor, ARL‐67156, blocks degradation of ADP more than the degradation of ATP in murine colon

Durnin

Moreland

Lees

et al. 2016

Neurogastroenterology Motil

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Background Adenosine 5’-triphosphate (ATP) is released extracellularly as a neurotransmitter and an autocrine or paracrine mediator in numerous systems, including the gastrointestinal tract. It is rapidly degraded to active and inactive metabolites by membrane-bound enzymes. Investigators frequently use inhibitors of ATP hydrolysis such as ARL-67156 and POM-1 to suppress the catabolism of ATP and prolong its effects in pharmacological studies. Our aim was to investigate directly the effects of ARL-67156 and POM-1 on the degradation of ATP and ADP in mouse colonic muscles. Methods The degradation of ATP and ADP was evaluated by superfusing tissues with 1,N6-etheno-ATP (eATP) and 1,N6-etheno-ADP (eADP) as substrates and monitoring the decrease of substrate and increase of products (i.e., eADP, eAMP, and e-adenosine) by high-performance liquid chromatography techniques with fluorescence detection. Relaxation responses to etheno-derivatized and non-derivatized ATP and ADP were examined in isometric tension experiments. Key results ARL-67156 inhibits the degradation of ADP but not of ATP whereas POM-1 inhibits the degradation of ATP but not of ADP in murine colonic muscles. Consequently, ARL-67156 enhances relaxation responses to both ATP and ADP whereas POM-1 reduces relaxation to ATP and does not affect relaxation to ADP. Conclusions & Inferences Studies that use ARL-67156 to inhibit ATP degradation in smooth muscle likely evaluate responses to accumulated ADP rather than ATP. POM-1 appears to be a more selective inhibitor of ATP degradation in the mouse colon. The choice of pharmacological tools in studies on extracellular ATP signaling may affect the interpretation of experimental data in functional studies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A commonly used ecto‐ATPase inhibitor, ARL‐67156, blocks degradation of ADP more than the degradation of ATP in murine colon

Durnin

Moreland

Lees

et al. 2016

Neurogastroenterology Motil

View full text Add to dashboard Cite

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“…However, Kitajima and co-workers have demonstrated that the α,β-Me-ATPinduced rise in the intracellular Ca 2+ in aortic smooth muscle cells is not entirely prevented by verapamil, which indicates the involvement of non-L-type voltage-dependent Ca 2+ channels and/or intracellular Ca 2+ release following P2Y receptor activation [30] . More recently, α,β-Me-ATP was demonstrated to activate the P2Y 1 receptor in the murine and human colon [31] . Indeed, in our study, both α,β-Me-ATP-induced relaxation and contraction were significantly reduced by the P2Y receptor blockers MRS2179, MRS2211 and MRS2500 and were …”

Section: P2y Receptors Involved In Purinergic Relaxation and Contractionmentioning

confidence: 99%

P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca2+ release and SK channel activation

et al. 2016

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Aim: Purinergic signaling plays a major role in the enteric nervous system, where it governs gut motility through a number of P2X and P2Y receptors. The aim of this study was to investigate the P2Y receptor-mediated motility in rat longitudinal ileum preparations. Methods: Ileum smooth muscle strips were prepared from rats, and fixed in an organ bath. Isometric contraction and relaxation responses of the muscle strips were measured with force transducers. Drugs were applied by adding of stock solutions to the organ bath to yield the individual final concentrations. Results: Application of the non-hydrolyzable P2 receptor agonists α,β-Me-ATP or 2-Me-S-ADP (10, 100 µmol/L) dose-dependently elicited a transient relaxation response followed by a sustained contraction. The relaxation response was largely blocked by SK channel blockers apamin (500 nmol/L) and UCL1684 (10 µmol/L), PLC inhibitor U73122 (100 µmol/L), IP 3 receptor blocker 2-APB (100 µmol/L) or sarcoendoplasmic Ca 2+ ATPase inhibitor thapsigargin (1 µmol/L), but not affected by atropine, NO synthase blocker L-NAME or tetrodotoxin. Furthermore, α,β-Me-ATP-induced relaxation was suppressed by P2Y 1 receptor antagonist MRS2179 (50 µmol/L) or P2Y 13 receptor antagonist MRS2211 (100 µmol/L), and was abolished by co-application of the two antagonists, whereas 2-Me-S-ADP-induced relaxation was abolished by P2Y 6 receptor antagonist MRS2578 (50 µmol/L). In addition, P2Y 1 receptor antagonist MRS2500 (1 µmol/L) not only abolished α,β-Me-ATP-induced relaxation, but also suppressed 2-Me-S-ADP-induced relaxation. Conclusion: P2Y receptor agonist-induced transient relaxation of rat ileum smooth muscle strips is mediated predominantly by P2Y 1 receptor, but also by P2Y 6 and P2Y 13 receptors, and involves PLC, IP 3 , Ca 2+ release and SK channel activation, but is independent of acetylcholine and NO release.

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Upregulated P2X3 Receptor Expression in Patients with Intractable Temporal Lobe Epilepsy and in a Rat Model of Epilepsy

Zhou

Xiong

et al. 2016

Neurochem Res

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Purinergic P2X3 receptors (P2X3Rs) play extensive roles in nerve cells in the central nervous system, particularly in hyperexcitability and calcium (Ca(2+)) influx. However, the role of P2X3Rs in epilepsy has not been previously investigated. To determine the relationship between P2X3Rs and epilepsy, the expression and cellular location of P2X3Rs in patients with intractable temporal lobe epilepsy (TLE) and in a lithium chloride-pilocarpine-induced chronic rat model of epilepsy were assessed. Furthermore, the function of P2X3Rs was assessed in vitro. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were used to evaluate the expression levels of P2X3Rs in brain tissues from TLE patients and an epileptic rat model, whereas immunofluorescence labeling was applied to determine the distribution of target proteins. Whole-cell recording was subsequently performed to identify the influence of P2X3Rs on seizure-like discharges. P2X3Rs were located at the cell bodies and dendrites of neurons with significantly increased expression in the TLE patients and epileptic rat model. In vitro, P2X3R activation accelerated sustained repetitive firing, whereas P2X3R inhibition led to relatively low-frequency discharges. To the best of our knowledge, this is the first study provide evidence that upregulated P2X3R expression exists in both epileptic humans and rats and may aggravate the epileptic state in vitro. Thus, P2X3Rs may represent a novel therapeutic target for antiepileptic drugs.

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α,β-meATP mimics the effects of the purinergic neurotransmitter in the human and rat colon

Cited by 14 publications

References 51 publications

A commonly used ecto‐ATPase inhibitor, ARL‐67156, blocks degradation of ADP more than the degradation of ATP in murine colon

A commonly used ecto‐ATPase inhibitor, ARL‐67156, blocks degradation of ADP more than the degradation of ATP in murine colon

P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca2+ release and SK channel activation

Upregulated P2X3 Receptor Expression in Patients with Intractable Temporal Lobe Epilepsy and in a Rat Model of Epilepsy

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