Journal article
Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut
Proceedings of the National Academy of Sciences - PNAS, Vol.111(44), pp.15821-15826
11/04/2014
DOI: 10.1073/pnas.1409078111
PMCID: PMC4226104
PMID: 25341729
Abstract
Enteric purinergic motor neurotransmission, acting through P2Y1 receptors (P2Y1R), mediates inhibitory neural control of the intestines. Recent studies have shown that NAD(+) and ADP ribose better meet criteria for enteric inhibitory neurotransmitters in colon than ATP or ADP. Here we report that human and murine colon muscles also release uridine adenosine tetraphosphate (Up4A) spontaneously and upon stimulation of enteric neurons. Release of Up4A was reduced by tetrodotoxin, suggesting that at least a portion of Up4A is of neural origin. Up4A caused relaxation (human and murine colons) and hyperpolarization (murine colon) that was blocked by the P2Y1R antagonist, MRS 2500, and by apamin, an inhibitor of Ca2+-activated small-conductance K+ (SK) channels. Up4A responses were greatly reduced or absent in colons of P2ry1(-/-) mice. Up4A induced P2Y1R-SK-channel-mediated hyperpolarization in isolated PDGFR alpha(+) cells, which are postjunctional targets for purinergic neurotransmission. Up4A caused MRS 2500-sensitive Ca2+ transients in human 1321N1 astrocytoma cells expressing human P2Y1R. Up4A was more potent than ATP, ADP, NAD(+), or ADP ribose in colonic muscles. In murine distal colon Up4A elicited transient P2Y1R-mediated relaxation followed by a suramin-sensitive contraction. HPLC analysis of Up4A degradation suggests that exogenous Up4A first forms UMP and ATP in the human colon and UDP and ADP in the murine colon. Adenosine then is generated by extracellular catabolism of ATP and ADP. However, the relaxation and hyperpolarization responses to Up4A are not mediated by its metabolites. This study shows that Up4A is a potent native agonist for P2Y1R and SK-channel activation in human and mouse colon.
Details
- Title: Subtitle
- Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut
- Creators
- Leonie Durnin - University of Nevada, Reno School of MedicineSung Jin Hwang - University of Nevada, Reno School of MedicineMasaaki Kurahashi - University of Nevada, Reno School of MedicineBernard T. Drumm - University of Nevada, Reno School of MedicineSean M. Ward - University of Nevada, Reno School of MedicineKent C. Sasse - Sasse Surgical Associates, Reno, NV 89502.Kenton M. Sanders - University of Nevada, Reno School of MedicineVioleta N. Mutafova-Yambolieva - University of Nevada, Reno School of Medicine
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.111(44), pp.15821-15826
- Publisher
- Natl Acad Sciences
- DOI
- 10.1073/pnas.1409078111
- PMID
- 25341729
- PMCID
- PMC4226104
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Number of pages
- 6
- Grant note
- R01 DK091336 / NIDDK; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) P01 DK41315 / National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) P01DK041315 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
- Language
- English
- Date published
- 11/04/2014
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984359781502771
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