Purinergic P2Y receptors: Molecular diversity and implications for treatment of cardiovascular diseases

Abstract

Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us understand the physiological and pathological significance of P2YRs in the cardiovascular system. P2YR-mediated biological functions are predominantly activated by mononucleotides released from non-adrenergic, non-cholinergic nerve endings or non-secretory tissues in response to physical stress or cell injury, though recent studies have suggested the occurrence of ligand-independent P2YR function through receptor-receptor interactions (oligomerization) in several biological processes. In this review, we introduce the functions of P2YRs and possible dimerization with G protein-coupled receptors (GPCRs) in the cardiovascular system. We focus especially on the crosstalk between uridine nucleotide-responsive P2YR and angiotensin (Ang) II type1 receptor (AT1R) signaling, and introduce our recent finding that the P2YR antagonist MRS2578 interrupts heterodimerization between P2YR and AT1R, thereby reducing the risk of AT1R-stimulated hypertension in mice. These results strongly suggest that targeting P2YR oligomerization could be an effective new strategy to reduce the risk of cardiovascular diseases.

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…The cellular sources of nucleotide agonists of P2Y receptors include co‐transmission, endocytosis, release through pannexin1 (Px1) hemichannels and lysis in cell damage (Abbracchio et al, 2006; Nishimura et al, 2017). The principal G protein coupling of each of the P2Y receptor subtypes are indicated in Table 1.…”

“…This review emphasizes the novel contribution of nucleotide receptors to maintain cell homeostasis through the regulation of MAPKs and phosphatases. P2Y receptors also undergo agonist‐induced desensitization and can heterodimerize with other GPCRs, such as the vascular angiotensin II AT 1 receptor and the A 1 adenosine receptor (Nishimura et al, 2017).…”

“…As such, they are involved in pathological processes such as acute vascular inflammation, atherosclerosis, arterial thrombosis including myocardial infarction, and cerebrovascular stroke. All the eight P2Y receptor subtypes have been found in the cardiovascular system, that is, in the heart, the vasculature, including smooth muscle cells and endothelial cells, or in blood cells (Nishimura et al, 2017). Studies using combined techniques, such as selective antagonists, or tissue selective or global P2Y receptor subtype deficient mice, helped to elucidate the role of these receptors in most aspects of the cardiovascular system.…”

“…The earliest papers on the role of adenine compounds by Drury and Szent‐Györgyi in 1929 reported on their effect on the mammalian heart. P2Y receptors , namely, P2Y 1 and P2Y 11 receptors, among other P2 receptor subtypes, including P2X receptors, are involved in cardiac function both indirectly via blood vessels and nerves and directly via the cardiomyocytes (Nishimura et al, 2017). These receptors have been reported to exert positive and negative inotropic effects as well as positive and negative chronotropic effects.…”

To Seek the Holy Grail of Cardiac Progenitor Cells

“…Accordingly, the purinergic receptor system has been implicated in platelet aggregation, inflammation, systemic arterial hypertension, atherosclerosis, cardiac contractility, hypertrophy, and heart failure. 10 …”