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

Abbas, Zainab S.B.; Latif, Muhammad Liaque; Dovlatova, Natalia; Fox, Sue C.; Heptinstall, Stan; Dunn, William R.; Ralevic, Vera

Abstract

Aims

UDP-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 results

Isometric 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 in 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.

Conclusions

Our 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.

Citation

Abbas, Z. S., Latif, M. L., Dovlatova, N., Fox, S. C., Heptinstall, S., Dunn, W. R., & Ralevic, V. (2018). UDP-sugars activate P2Y 14 receptors to mediate vasoconstriction of the porcine coronary artery. Vascular Pharmacology, 103-105, https://doi.org/10.1016/j.vph.2017.12.063

• Journal Article Type: Article
• Acceptance Date: Dec 12, 2017
• Online Publication Date: Dec 15, 2017
• Publication Date: Apr 30, 2018
• Deposit Date: Jan 9, 2018
• Publicly Available Date: Jan 9, 2018
• Journal: Vascular Pharmacology
• Print ISSN: 1537-1891
• Electronic ISSN: 1879-3649
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 103-105
• DOI: https://doi.org/10.1016/j.vph.2017.12.063
• Keywords: Coronary artery; P2Y6 receptor; P2Y14 receptor; UDP-glucose; UDP sugars; MRS2690; Sugar nucleotides
• Public URL: https://nottingham-repository.worktribe.com/output/929261
• Publisher URL: https://doi.org/10.1016/j.vph.2017.12.063