How selective antagonists and genetic modification have helped characterise the expression and functions of vascular P2Y receptors.

IF 3 4区 医学 Q2 NEUROSCIENCES Purinergic Signalling Pub Date : 2024-05-13 DOI:10.1007/s11302-024-10016-z
Markie O Dales, Robert M Drummond, Charles Kennedy
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Abstract

Vascular P2Y receptors mediate many effects, but the role of individual subtypes is often unclear. Here we discuss how subtype-selective antagonists and receptor knockout/knockdown have helped identify these roles in numerous species and vessels. P2Y1 receptor-mediated vasoconstriction and endothelium-dependent vasodilation have been characterised using the selective antagonists, MRS2179 and MRS2216, whilst AR-C118925XX, a P2Y2 receptor antagonist, reduced endothelium-dependent relaxation, and signalling evoked by UTP or fluid shear stress. P2Y2 receptor knockdown reduced endothelial signalling and endothelial P2Y2 receptor knockout produced hypertensive mice and abolished vasodilation elicited by an increase in flow. UTP-evoked vasoconstriction was also blocked by AR-C118925XX, but the effects of P2Y2 receptor knockout were complex. No P2Y4 receptor antagonists are available and P2Y4 knockout did not affect the vascular actions of UTP and UDP. The P2Y6 receptor antagonist, MRS2578, identified endothelial P2Y6 receptors mediating vasodilation, but receptor knockout had complex effects. MRS2578 also inhibited, and P2Y6 knockout abolished, contractions evoked by UDP. P2Y6 receptors contribute to the myogenic tone induced by a stepped increase in vascular perfusion pressure and possibly to the development of atherosclerosis. The P2Y11 receptor antagonists, NF157 and NF340, inhibited ATP-evoked signalling in human endothelial cells. Vasoconstriction mediated by P2Y12/P2Y13 and P2Y14 receptors was characterised using the antagonists, cangrelor, ticagrelor, AR-C67085 and MRS2211 or PPTN respectively. This has yet to be backed up by receptor knockout experiments. Thus, subtype-selective antagonists and receptor knockout/knockdown have helped identify which P2Y subtypes are functionally expressed in vascular smooth muscle and endothelial cells and the effects that they mediate.

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选择性拮抗剂和基因改造如何帮助确定血管 P2Y 受体的表达和功能特征。
血管 P2Y 受体介导多种效应,但各个亚型的作用往往不明确。在此,我们将讨论亚型选择性拮抗剂和受体敲除/敲减如何帮助确定这些受体在许多物种和血管中的作用。P2Y1受体介导的血管收缩和内皮依赖性血管舒张已通过选择性拮抗剂MRS2179和MRS2216进行了表征,而P2Y2受体拮抗剂AR-C118925XX可减少内皮依赖性松弛以及UTP或流体剪切应力诱发的信号传导。P2Y2 受体敲除可减少内皮信号传导,内皮 P2Y2 受体敲除可产生高血压小鼠,并消除血流增加引起的血管舒张。AR-C118925XX 也能阻断UTP 诱导的血管收缩,但 P2Y2 受体敲除的影响是复杂的。目前还没有 P2Y4 受体拮抗剂,P2Y4 基因敲除并不影响UTP 和 UDP 对血管的作用。P2Y6 受体拮抗剂 MRS2578 发现了介导血管扩张的内皮 P2Y6 受体,但受体敲除的影响很复杂。MRS2578 还能抑制 UDP 诱导的收缩,而 P2Y6 受体敲除则能消除这种收缩。P2Y6 受体有助于血管灌注压阶梯式增加所诱导的肌张力,也可能有助于动脉粥样硬化的发展。P2Y11 受体拮抗剂 NF157 和 NF340 可抑制人内皮细胞中 ATP 诱导的信号传导。分别使用坎格雷罗、替卡格雷罗、AR-C67085 和 MRS2211 或 PPTN 等拮抗剂对 P2Y12/P2Y13 和 P2Y14 受体介导的血管收缩进行了表征。这还需要受体敲除实验的支持。因此,亚型选择性拮抗剂和受体剔除/敲除有助于确定哪些 P2Y 亚型在血管平滑肌和内皮细胞中有功能表达,以及它们介导的效应。
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来源期刊
Purinergic Signalling
Purinergic Signalling 医学-神经科学
CiteScore
6.60
自引率
17.10%
发文量
75
审稿时长
6-12 weeks
期刊介绍: Nucleotides and nucleosides are primitive biological molecules that were utilized early in evolution both as intracellular energy sources and as extracellular signalling molecules. ATP was first identified as a neurotransmitter and later as a co-transmitter with all the established neurotransmitters in both peripheral and central nervous systems. Four subtypes of P1 (adenosine) receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of P2Y G protein-coupled receptors have currently been identified. Since P2 receptors were first cloned in the early 1990’s, there is clear evidence for the widespread distribution of both P1 and P2 receptor subtypes in neuronal and non-neuronal cells, including glial, immune, bone, muscle, endothelial, epithelial and endocrine cells.
期刊最新文献
Correction to: Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist. Machine learning-aided search for ligands of P2Y6 and other P2Y receptors. Purinergic regulation of pulmonary vascular tone. Role of ecto-5'-nucleotidase in bladder function activity and smooth muscle contractility. Unexpected role of microglia and P2Y12 in the induction of and emergence from anesthesia.
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