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 Ca(2+)-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 PDGFRα(+) cells, which are postjunctional targets for purinergic neurotransmission. Up4A caused MRS 2500-sensitive Ca(2+) 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.
Pharmacology, Toxicology and Pharmaceutical Science
2
6%
Immunology and Microbiology
2
6%
Other
6
19%
Unknown
7
23%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 12. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 February 2022.
All research outputs
#4,066,812
of 34,297,219 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#42,345
of 118,714 outputs
Outputs of similar age
#38,227
of 307,736 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#482
of 958 outputs
Altmetric has tracked 34,297,219 research outputs across all sources so far. Compared to these this one has done well and is in the 88th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 118,714 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 39.9. This one has gotten more attention than average, scoring higher than 64% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 307,736 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 87% of its contemporaries.
We're also able to compare this research output to 958 others from the same source and published within six weeks on either side of this one. This one is in the 48th percentile – i.e., 48% of its contemporaries scored the same or lower than it.
