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Novel vasocontractile role of the P2Y14receptor: characterization of its signalling in porcine isolated pancreatic arteries

Alsaqati, M.; Latif, M.L.; Chan, S.L.F.; Ralevic, V.

Authors

M. Alsaqati

M.L. Latif

SUE CHAN sue.chan@nottingham.ac.uk
Associate Professor

VERA RALEVIC vera.ralevic@nottingham.ac.uk
Associate Professor & Reader in Cardiovascular Sciences



Abstract

Background and Purpose: The P2Y14 receptor is the newest member of the P2Y receptor family; it is Gi/o protein-coupled and is activated by UDP and selectively by UDP-glucose and MRS2690 (2-thiouridine-5′-diphosphoglucose) (7–10-fold more potent than UDP-glucose). This study investigated whether P2Y14 receptors were functionally expressed in porcine isolated pancreatic arteries.
Experimental Approach: Pancreatic arteries were prepared for isometric tension recording and UDP-glucose, UDP and MRS2690 were applied cumulatively after preconstriction with U46619, a TxA2 mimetic. Levels of phosphorylated myosin light chain 2 (MLC2) were assessed with Western blotting. cAMP concentrations were assessed using a competitive enzyme immunoassay kit.
Key Results: Concentration-dependent contractions with a rank order of potency of MRS2690 (10-fold) > UDP-glucose ≥ UDP were recorded. These contractions were reduced by PPTN {4-[4-(piperidin-4-yl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthoic acid}, a selective antagonist of P2Y14 receptors, which did not affect responses to UTP. Contraction to UDP-glucose was not affected by MRS2578, a P2Y6 receptor selective antagonist. Raising cAMP levels and forskolin, in the presence of U46619, enhanced contractions to UDP-glucose. In addition, UDP-glucose and MRS2690 inhibited forskolin-stimulated cAMP levels. Removal of the endothelium and inhibition of endothelium-derived contractile agents (TxA2, PGF2α and endothelin-1) inhibited contractions to UDP glucose. Y-27632, nifedipine and thapsigargin also reduced contractions to the agonists. UDP-glucose and MRS2690 increased MLC2 phosphorylation, which was blocked by PPTN.
Conclusions and Implications: P2Y14 receptors play a novel vasocontractile role in porcine pancreatic arteries, mediating contraction via cAMP-dependent mechanisms, elevation of intracellular Ca2+ levels, activation of RhoA/ROCK signalling and MLC2, along with release of TxA2, PGF2α and endothelin-1.

Citation

Alsaqati, M., Latif, M., Chan, S., & Ralevic, V. (2014). Novel vasocontractile role of the P2Y14receptor: characterization of its signalling in porcine isolated pancreatic arteries. British Journal of Pharmacology, 171(3), https://doi.org/10.1111/bph.12473

Journal Article Type Article
Acceptance Date Oct 9, 2013
Online Publication Date Jan 13, 2014
Publication Date Feb 4, 2014
Deposit Date Jul 11, 2016
Publicly Available Date Jul 11, 2016
Journal British Journal of Pharmacology
Print ISSN 0007-1188
Electronic ISSN 0007-1188
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 171
Issue 3
DOI https://doi.org/10.1111/bph.12473
Keywords UDP-glucose; UDP;MRS2690; P2Y14 receptor; vasoconstriction; endothelium
Public URL http://eprints.nottingham.ac.uk/id/eprint/34818
Publisher URL http://onlinelibrary.wiley.com/doi/10.1111/bph.12473/abstract;jsessionid=804DA88F606FEAA0EC72BFAE4C608687.f01t02
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc/4.0
Additional Information This is the peer reviewed version of the following article: Alsaqati, M., Latif, M. L., Chan, S. L. F. and Ralevic, V. (2014), Novel vasocontractile role of the P2Y14 receptor: characterization of its signalling in porcine isolated pancreatic arteries. British Journal of Pharmacology, 171: 701–713. doi: 10.1111/bph.12473, which has been published in final form at http://onlinelibrary.wi.../doi/10.1111/bph.12473. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc/4.0





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