Potential therapeutic targets in the rapidly expanding field of purinergic signalling

Abstract

-The concept of a purinergic signalling system, using purine nucleotides and nucleosides as extracellular messengers, was first proposed over 30 years ago. After a brief historical review and update of purinoceptor subtypes, this article focuses on the diverse physiological roles of adenosine triphosphate, adenosine diphosphate, uridine triphosphate and adenosine. These molecules mediate short-term (acute) signalling functions in neurotransmission, secretion and vasodilation, and long-term (chronic) signalling functions in development, regeneration, proliferation and cell death. Plasticity of purinoceptor expression in pathological conditions is frequently obser ved, including an increase in the purinergic component of parasympathetic nervous control of the human bladder in interstitial cystitis and outflow obstruction, and in sympathetic cotransmitter control of blood vessels in hypertensive rats. The antithrombotic action of clopidogrel (Plavix), a P2Y 12 receptor antagonist, has been shown to be particularly promising in the prevention of recurrent strokes and heart attacks in recent clinical trials (CAPRIE and CURE). The role of P2X 3 receptors in nociception and a new hypothesis concerning purinergic mechanosensory transduction in visceral pain will be considered, as will the therapeutic potential of purinergic agonists or antagonists for the treatment of supraventricular tachycardia, cancer, dry eye, bladder hyperactivity, erectile dysfunction, osteoporosis, diabetes, gut motility and vascular disorders. KEY WORDS: purinoceptors, interstitial cystitis, thrombosis, visceral pain, cancer, osteoporosis, peripheral vascular disease, cystic fibrosis, Parkinson' s disease, kidney failure Purinergic signalling: history and receptor subtypes A seminal paper by Drury and Szent-Györgi in 1929 described the potent actions of purine nucleotides and nucleosides, adenosine triphosphate (ATP) and adenosine on the heart and blood vessels 1 . A landmark paper by Pamela Holton in 1959 showed that, during antidromic stimulation of sensory nerves, ATP was released to the rabbit ear artery in sufficient amounts to produce changes in vascular tone 2 . Then, in 1970, Burnstock et al. found evidence for the role of ATP as a neurotransmitter in nonadrenergic, noncholinergic (NANC) nerves supplying the gut 3 , and, in 1972, the word 'purinergic' was coined and the purinergic-neurotransmission hypothesis was put forward 4 (Fig 1). This concept met with considerable resistance for many years because ATP had been established as an intracellular energy source involved in various metabolic cycles, and it was thought that such a ubiquitous molecule was unlikely to be involved in selective extracellular signalling. However, the concept is now widely accepted. Later, it was established that ATP is a cotransmitter with classical transmitters in both the peripheral and the central nervous systems, and that purines are powerful extracellular messengers to non-neuronal cells, including exocrine and endocrine, secretory, endothelial, b...

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

“…4a). This result was confirmed by quantitative analysis of the ecto-5′-NT/CD73 immunofluorescence, which increased in a time-response profile of BBN exposition (4,8,12,18, and 24 weeks). Moreover, it was observed that an increase in the areas of increased cell proliferation and decreased presence of umbrella cells are important pathological characteristics of a malignant bladder process.…”

“…White scale bars= 25 μm. b Quantification of ecto-5′-NT/CD73 staining of bladder urothelium from mice which received BBN for 4,8,12,18, and 24 weeks. The immunofluorescent images of ecto-5′-NT/CD73 were quantified in MacBiophotonics ImageJ software as described in Materials and methods.…”

“…In this work, bladder cancer was induced by the addition of 0.05 % of BBN in the drinking water for 4,8,12,18, and 24 weeks with a respective control group for each induction time. The number of mice per group was 8 for control groups of 4, 8, and 12 weeks and 9, 10, and 10 for BBN groups of 4, 8, and 12 weeks, respectively; and for the cancer induction times of 18 and 24 weeks, it was 3 for control groups and 5 and 4 for groups that received BBN, respectively.…”

“…Accordingly, recent researches have focused in the potential involvement of purinergic system in bladder tumors [1,[12][13][14]. Nucleosides and nucleotides mediate a variety of biological functions in both short-and long-term signaling functions (development, regeneration, differentiation, proliferation, and cell death) [1,12].…”

“…Nucleosides and nucleotides mediate a variety of biological functions in both short-and long-term signaling functions (development, regeneration, differentiation, proliferation, and cell death) [1,12]. These events are mediated by the activation of P1 (for adenosine) or P2 (for ATP, ADP, UDP, and UTP) receptors and are controlled by the action of ectonucleotidases [15].…”