UDP-glucose modulates gastric function through P2Y14 receptor-dependent and -independent mechanisms.
P2Y receptors have been reported to modulate gastrointestinal functions. The newest family member is the nucleotide-sugar receptor P2Y14. P2ry14 mRNA was detected throughout the rat gut, with the highest level being in the forestomach. We investigated the role of the receptor in stomach motility using cognate agonists and knockout (KO) mice. In rat isolated forestomach, 100 microM UDP-glucose and 100 muM UDP-galactose both increased the baseline muscle tension (BMT) by 6.2+/-0.6 and 1.6+/-0.6 mN (P<0.05, n=3-4), respectively, and the amplitude of contractions during electrical field stimulation (EFS) by 3.7+/-1.7 and 4.3+/-2.5 mN (P<0.05, n=3-4), respectively. In forestomach from wild-type (WT) mice, 100 microM UDP-glucose increased the BMT by 1.0+/-0.1 mN (P<0.05, n=6) but this effect was lost in the KO mice (change of -0.1+/-0.1 mN, n=6). The 100 microM UDP-glucose also increased the contraction amplitude during EFS in this tissue from the WT animals (0.9+/-0.4 mN, P < 0.05, n=6) but not from the KO mice (0.0+/-0.2 mN, n=6). In vivo, UDP-glucose at 2,000 mg/kg ip reduced gastric emptying in rats by 49.7% (P<0.05, n=4-6) and in WT and KO mice by 56.1 and 66.2%, respectively (P<0.05, n=7-10) vs. saline-treated control animals. There was no significant difference in gastric emptying between WT and KO animals receiving either saline or d-glucose. These results demonstrate a novel function of the P2Y14 receptor associated with contractility in the rodent stomach that does not lead to altered gastric emptying after receptor deletion and an ability of UDP-glucose to delay gastric emptying without involving the P2Y14 receptor.
Bassil
Anna K
AK
Department of Gastrointestinal Research, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, Harlow, UK.
Bourdu
Sophie
S
Townson
Karen A
KA
Wheeldon
Alan
A
Jarvie
Emma M
EM
Zebda
Noureddine
N
Abuin
Alejandro
A
Grau
Evelyn
E
Livi
George P
GP
Punter
Lorraine
L
Latcham
Judith
J
Grimes
Angela M
AM
Hurp
David P
DP
Downham
Kelly M
KM
Sanger
Gareth J
GJ
Winchester
Wendy J
WJ
Morrison
Alastair D
AD
Moore
Gary B T
GB
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000502:physiology; D007763:Lac Operon / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y; D014531:Uridine Diphosphate Galactose / Q000494:pharmacology; D014532:Uridine Diphosphate Glucose / Q000494:pharmacology*
C528912:P2Y14 receptor, rat; C509795:P2ry14 protein, mouse; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058470:Receptors, Purinergic P2Y; D014531:Uridine Diphosphate Galactose; D014532:Uridine Diphosphate Glucose