Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut

Durnin, Leonie; Hwang, Sung Jin; Kurahashi, Masaaki; Drumm, Bernard T.; Ward, Sean M.; Sasse, Kent C.; Sanders, Kenton M.; Mutafova‐Yambolieva, Violeta N.

doi:10.1073/pnas.1409078111

Cited by 33 publications

(38 citation statements)

References 29 publications

(47 reference statements)

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“…Furthermore, vasoconstriction was observed in mouse renal arterioles (7) and aorta (8). Although, there is evidence that Up 4 A can produce vasodilation in isolated aortic rings of rats (5), porcine coronary small arteries (11, 12), human and mouse colon (30) as well as induce hypotension in conscious rats (8). All together, these studies suggest that the vascular responses to Up 4 A likely depend on the type of vascular beds and species studied (4).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, Up 4 A induces vasoconstriction in rat perfused kidney through P2X 1 R and P2Y 1 R (10), in rat aorta through P1R and P2XR (5), and in rat pulmonary arteries through P2YR (6), while Up 4 A produces vasodilation in rat perfused kidney through P2Y 1 R and P2Y 2 R (10), in porcine coronary arteries through A 2A AR, P2X 1 R and P2Y 1 R (12) and in human and mouse colon through P2Y 1 R (30). Surprisingly, Up 4 A-mediated vascular contraction in mouse aorta in the present study was not affected by A 3 AR deletion, although one of our previous observations showed that activation of A 3 AR contributes to mouse aortic contraction (19).…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

Zhou

Sun

Tilley

et al. 2015

Vascular Pharmacology

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Uridine adenosine tetraphosphate (Up4A), a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorders and induces aortic contraction through activation of cyclooxygenases (COX). We and others demonstrated that activation of A1 or A3 adenosine receptors (AR) results in vascular contraction via thromboxane (TX) A2 production. However, the mechanisms of Up4A-induced vascular contraction in mouse aorta are not understood. We hypothesize that Up4A-induced aortic contraction is through COX-derived TXA2 production, which requires activation of A1 and/or A3AR. Concentration responses to Up4A were conducted in isolated aorta. The TXB2 production, a metabolite of TXA2, was also measured. Up4A (10−9–10−5 M) produced a concentration-dependent contraction >70%, which was markedly attenuated by COX and COX1 but not by COX2 inhibition. Notably, Up4A-induced aortic contraction was blunted by both TX synthase inhibitor ozagrel and TXA2 receptor (TP) antagonist SQ29548. Surprisingly, A3AR deletion had no effect on Up4A-induced contraction. Moreover, A1AR deletion or antagonism as well as A1/A3AR deletion potentiated Up4A-induced aortic contraction, suggesting a vasodilator influence of A1AR. In contrast, non-selective purinergic P2 receptor antagonist PPADS significantly blunted Up4A-induced aortic contraction to a similar extent as selective P2X1R antagonist MRS2159, the latter of which was further reduced by addition of ozagrel. Endothelial denudation almost fully attenuated Up4A-induced contraction. Furthermore, Up4A (3 µM) increased TXB2 formation, which was inhibited by either MRS2159 or ozagrel. In conclusion, Up4A-induced aortic contraction depends on activation of TX synthase and TP, which partially requires the activation of P2X1R but not A1 or A3 AR through an endothelium-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

Zhou

Sun

Tilley

et al. 2015

Vascular Pharmacology

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“…A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. For example, P 1 -(59-adenosinyl)-P 4 -(59-uridinyl)-tetraphosphate (Up 4 A) is released from the vascular endothelium to induce vasoconstriction and has been explored in various biologic contexts, such as P2Y 2 R-induced migration of smooth muscle cells and activation of enteric neuronal P2Y 1 R (Wiedon et al, 2012;Durnin et al, 2014). Diadenosine polyphosphates, such as Ap 4 A, are plentiful in platelet granules and secretory granules of nerve terminals.…”

Section: Introductionmentioning

confidence: 99%

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

et al. 2015

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Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y 2 and P2Y 11 ), ADP (P2Y 1 , P2Y 12 , and P2Y 13 ), UTP (P2Y 2 and P2Y 4 ), UDP (P2Y 6 and P2Y 14 ), and UDP glucose (P2Y 14 ). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the G i -coupled P2Y 12 R and two of the G q -coupled P2Y 1 Rs were recently determined and will be especially useful in structure-based ligand design at two P2YR subfamilies. These high-resolution structures, which display unusual binding site features, complement mutagenesis studies for probing ligand recognition and activation. The structural requirements for nucleotide agonist recognition at P2YRs are relatively permissive with respect to the length of the phosphate moiety, but less so with respect to base recognition. Nucleotide-like antagonists and partial agonists are also known for P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 12 Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists, such as dinucleotides, typically, dinucleoside triphosphates or tetraphosphates, and nucleoside polyphosphate sugars (e.g., UDP glucose) as well as the more conventional mononucleotide agonists. A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. Earlier modeling predictions of the P2YRs were not very accurate, but recent findings have provided much detailed structural insight into this receptor family to aid in the rational design of new drugs.

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“…Each of these has greater or lesser affinity for the different purine receptors subtypes (31). It was recently hypothesized that β-NAD (β-nicotinamide adenine dinucleotide), ADPR (ADP ribose) or Up4A (uridine adenosine tetraphosphate) might be (even instead of ATP) the purinergic neurotransmitter in the GI tract (46)(47)(48)(49). However, some experimental data have nuanced these results (43,50-52).…”

Section: Atp and Maybe Other Neurotransmitters?mentioning

confidence: 99%

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

Gallego¹,

Mañé²,

Gil³

et al. 2016

Rev Esp Enferm Dig

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The enteric nervous system (ENS) is responsible for the genesis of motor patterns ensuring an appropriate intestinal transit. Enteric motor neurons are classified into afferent neurons, interneurons and motorneurons. Motorneurons are excitatory or inhibitory causing smooth muscle contraction and relaxation respectively. Muscle relaxation mechanisms are key for the understanding of physiological processes such as sphincter relaxation, gastric accommodation, or the descending phase of the peristaltic reflex. Nitric oxide (NO) and ATP or a related purine are the primary inhibitory neurotransmitters. Nitrergic neurons synthesize NO through nNOS enzyme activity. NO diffuses across the cell membrane to bind guanylyl cyclase, and then activates a number of intracellular mechanisms that ultimately result in muscle relaxation. ATP is an inhibitory neurotransmitter together with NO. The P2Y1 receptor has been identified as a the purine receptor responsible for smooth muscle relaxation. Although, probably, no clinician doubts about the significance of NO in the pathophysiology of gastrointestinal motility, the relevance of purinergic neurotransmission is apparently much lower, as ATP has not been associated with any specific motor dysfunction yet. The goal of this review is to discuss the function of both relaxation mechanisms in order to establish the physiological grounds of potential motor dysfunctions arising from impaired intestinal relaxation.

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Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut

Abstract: www.pnas.org PNAS |

Cited by 33 publications

References 29 publications

Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

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