UDP-sugars activate P2Y 14 receptors to mediate vasoconstriction of the porcine coronary artery

Abstract

AimsUDP-sugars can act as extracellular signalling molecules, but relatively little is known about their cardiovascular actions. The P2Y14 receptor is a Gi/o-coupled receptor which is activated by UDP-glucose and related sugar nucleotides. In this study we sought to investigate whether P2Y14 receptors are functionally expressed in the porcine coronary artery using a selective P2Y14 receptor agonist, MRS2690, and a novel selective P2Y14 receptor antagonist, PPTN (4,7-disubstituted naphthoic acid derivative).Methods and resultsIsometric tension recordings were used to evaluate the effects of UDP-sugars in porcine isolated coronary artery segments. The effects of the P2 receptor antagonists suramin and PPADS, the P2Y14 receptor antagonist PPTN, and the P2Y6 receptor antagonist MRS2578, were investigated. Measurement of vasodilator-stimulated phosphoprotein (VASP) phosphorylation using flow cytometry was used to assess changes in cAMP levels. UDP-glucose, UDP-glucuronic acid UDP-N-acetylglucosamine (P2Y14 receptor agonists), elicited concentration-dependent contractions of the porcine coronary artery. MRS2690 was a more potent vasoconstrictor than the UDP-sugars. Concentration dependent contractile responses to MRS2690 and UDP-sugars were enhanced in the presence of forskolin (activator of cAMP), where the level of basal tone was maintained by addition of U46619, a thromboxane A2 mimetic. Contractile responses to MRS2690 were blocked by PPTN, but not by MRS2578. Contractile responses to UDP-glucose were also attenuated by PPTN and suramin, but not by MRS2578. Forskolin-induced VASP-phosphorylation was reduced in porcine coronary arteries exposed to UDP-glucose and MRS2690, consistent with P2Y14 receptor coupling to Gi/o proteins and inhibition of adenylyl cyclase activity.ConclusionsOur data support a role of UDP-sugars as extracellular signalling molecules and show for the first time that they mediate contraction of porcine coronary arteries via P2Y14 receptors.

Sleep fragmentation increases blood pressure and is associated with alterations in the gut microbiome and fecal metabolome in rats

“…UDP-glucose fecal metabolite levels were positively associated with increased MAP in both SF and control rats, and fecal UDP-glucose levels were significantly lower in SF rats versus control rats during the recovery/rest period ( day 34 ). To our knowledge, no research has linked UDP-glucose and MAP outcomes, but UDP-glucose has been shown to produce porcine artery vasoconstriction through its action on P2Y 14 receptors ( 1 , 3 ). UDP-glucose’s vasoactive properties through cAMP-dependent signaling ( 3 ), and association with increased MAP suggests that this metabolite could be a promising target of future gut microbiota-linked hypertension research.…”

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…UDP and sugar derivatives such as UDP‐glucose and UDP‐galactose are G i ‐coupled P2Y 14 receptor agonists (Abbracchio et al, 2006, 2019; Carter et al, 2009). The analogues MRS2690 (diphosphoric acid 1‐α‐ d ‐glucopyranosyl ester 2‐[(4′‐methylthio)uridin‐5″‐yl] ester, 43 ), MRS2802 (α,β‐difluoromethylene‐UDP, 44 ), and MRS2905 (α,β‐methylene‐2‐thio‐UDP, 45 ) are much more potent agonists (Abbas et al, 2018; Carter et al, 2009; Das et al, 2010).…”

Role of P2Y Receptors in Platelet Extracellular Vesicle Release

“…For example, the P2Y14 receptors contribute to chemotaxis in human neutrophils [ 5 ]. Historically, the P2Y14 receptors were thought to be strictly uracil-diphosphate (UDP)-glucose-activated, while newer studies have suggested that UDP is also a potent agonist of these receptors [ 8 , 9 ]. At present, there is no evidence that the P2Y14 receptors are activated by ADP [ 51 ].…”

“…In turn, the P2Y13 receptor is mostly involved into cholesterol and glucose metabolism, bone homeostasis, pain transmission, and neuroprotection in central nervous system, whereas its role in platelet activation has not yet been established [ 6 , 7 ]. On the other hand, the P2Y14 receptor mediates vasoconstriction of the smooth muscle cells [ 9 ]. The P2Y1 and P2Y12 receptors are purinergic G protein-coupled receptors for ADP that are widely distributed within cells, including platelets [ 10 ].…”