Abstract
Adenosine triphosphate (ATP) is a primordial versatile autacoid that changes its role from an intracellular energy saver to a signaling molecule once released to the extracellular milieu. Extracellular ATP and its adenosine metabolite are the main activators of the P2 and P1 purinoceptor families, respectively. Mounting evidence suggests that the ionotropic P2X4 receptor (P2X4R) plays pivotal roles in the regulation of the cardiovascular system, yet further therapeutic advances have been hampered by the lack of selective P2X4R agonists. In this review, we provide the state of the art of the P2X4R activity in the cardiovascular system. We also discuss the role of P2X4R activation in kidney and lungs vis a vis their interplay to control cardiovascular functions and dysfunctions, including putative adverse effects emerging from P2X4R activation. Gathering this information may prompt further development of selective P2X4R agonists and its translation to the clinical practice.
Highlights
The concept of “purinome” encompasses the molecular machinery necessary for purinergic signaling
Our study demonstrated for the first time that rather than requiring its breakdown to adenosine, Adenosine triphosphate (ATP) on its own is able to decrease chronotropy via P2X4 receptor (P2X4R) activation
Pushed by the success of P2Y12 receptor antagonists as anti-thrombotic drugs, last decades have provided new experimental and pharmacological tools to dissect the purinergic signaling cascade, including the purinoceptors function, which have granted a series of promising druggable targets, and some of them were already admitted to clinical trials
Summary
The concept of “purinome” encompasses the molecular machinery necessary for purinergic signaling The core of this system is adenine nucleotides and nucleosides and their activity over a wide range of transmembrane purinoceptors. Despite the lack of selective P2X4R agonists available so far, modulation of the P2X4R has been demonstrated to be beneficial in cardiac diseases, pain sensation, cancer, and inflammatory diseases [8,9]. Due to these putative therapeutic hints, we expect a boost in the development of selective P2X4R agonists in the forthcoming years. Considering that impairment of other body systems (e.g., renal and respiratory) might have a huge impact in the management and prognosis of cardiac patients, we thought it was useful to discuss the (beneficial and/or detrimental) repercussions of the P2X4R activation in these territories
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