From purines to purinergic signalling: molecular functions and human diseases

Abstract

Purines and their derivatives, most notably adenosine and ATP, are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis. Besides, these purines support, as chemical messengers, purinergic transmission throughout tissues and species. Purines act as endogenous ligands that bind to and activate plasmalemmal purinoceptors, which mediate extracellular communication referred to as "purinergic signalling". Purinergic signalling is cross-linked with other transmitter networks to coordinate numerous aspects of cell behaviour such as proliferation, differentiation, migration, apoptosis and other physiological processes critical for the proper function of organisms. Pathological deregulation of purinergic signalling contributes to various diseases including neurodegeneration, rheumatic immune diseases, inflammation, and cancer. Particularly, gout is one of the most prevalent purine-related disease caused by purine metabolism disorder and consequent hyperuricemia. Compelling evidence indicates that purinoceptors are potential therapeutic targets, with specific purinergic agonists and antagonists demonstrating prominent therapeutic potential. Furthermore, dietary and herbal interventions help to restore and balance purine metabolism, thus addressing the importance of a healthy lifestyle in the prevention and relief of human disorders. Profound understanding of molecular mechanisms of purinergic signalling provides new and exciting insights into the treatment of human diseases.

Fig. 1

The causative role of purinergic signalling in human diseases. Purinoceptors, including P1, P2X and P2Y receptors, are diffusely expressed in every human body part, such as the nervous system, circulatory system, respiratory system, immune system, urinary system and others. Dysregulation of purinoceptors function leads to various diseases, including neurological, rheumatic, cardiovascular, cancer diseases and so on

Fig. 2

De novo and salvage pathway for purine synthesis. PRPP generated from glycolysis and pentose phosphate pathway (green) serves as substrate for de novo purine synthesis (blue background). After 10-step reaction catalysed by six enzymes with different functional domains, IMP is produced as the end of de novo pathway. Salvage pathway (orange background) is mainly catalysed by two enzymes, namely HPRT and APRT. In this pathway, PRPP is also needed, and several nucleosides serve as co-substrates for the production of nucleotides. The final metabolite uric acid is further oxidised by uricase (grey), which is expressed in most organisms but lost in humans and a part of primates

Fig. 3

Dysregulated purine metabolism contributes to gout and pain. Purine-rich diet and several beverages, including meat, seafood, animal offal, beer and fructose containing drinks, lead to high level of uric acid in vessel, termed hyperuricemia. Deposition of urate in joint induces local inflammation. In this process, adenosine (ADO) and ATP function as neurotransmitters to activate P1 and P2 purinergic receptors, respectively. This purinergic neurotransmission induces intense pain in gout patients

Fig. 4

Purinoceptors mediates neurotransmission in nervus system. In presynaptic terminal, ATP is enriched in vesicles by transporter VNUT and then released in a Ca²⁺-dependent manner, or exported by other channels such as Panx1 independent of Ca²⁺. On one hand, extracellular ATP and its degradation product adenosine in turn activate purinoceptors in presynaptic terminal. This effect may regulate the release of other transmitters such as glutamate. On the other hand, extracellular ATP and adenosine can interact with postsynaptic purinoceptors, thereby regulating the excitability of neural cells. This event might also lead to the internalisation of AMPAR and NMDAR on postsynaptic membrane, leading to a decrease of glutamate-induced current. VNUT vesicular nucleotide transporter, Panx1 pannexin 1, AD adenosine, AMPAR AMPA receptor, NMDAR N-methyl-d-aspartate receptor

Fig. 5

Purinergic signalling regulates immune and inflammatory responses. Besides necrotic cells, extracellular ATP can be released from living cells through Panx1 channel. Extracellular ATP activates P2X₇ receptors, which subsequently activate NLRP3 inflammasome to induce the cleavage of pro-caspase-1. This effect leads to the maturation and release of caspase-1 thus initiating an immune or inflammatory response. Alternatively, extracellular ATP is ready to be degraded into adenosine (ADO) by ectoenzymes such as CD39 and CD73. The production of adenosine generally represses immune and inflammatory through binding with P1 receptors. In addition, P2X₇ can be activated by ADP-ribosylation using NAD⁺ as an ADP-ribose donor

Fig. 6

Purinergic signalling involved in the initiation and progression of cancer. Tumour microenvironment is rich in purines, including adenosine (AD) and other nucleotides. A panel of purinergic receptors are expressed in tumour cells to receive these extracellular purinergic signals. Activation of P1 and P2Y receptors leads to an altered activity of adenylate cyclase or phospholipase C (PLC) by coupling different G proteins (G), whereas activation of P2X receptors generates ion fluxes. These events change the level of several secondary messengers, such as cAMP, Ca²⁺ and InsP₃. InsP₃ binds to the InsP₃ receptors on endoplasmic reticulum (ER), leading to the release of Ca²⁺ from ER. Thus, numerous proteins are regulated by these secondary messengers, including PKA, PKC, GSK3β, CREB, androgen receptor (AR), MEK, p38, ERK and ATF2. Among them are several transcription factors such as CREB, AR and ATF2, which induce a cancer-related transcription programme

Fig. 7

Traditional Chinese medicine and evidence-based medicine with therapeutic potential for purine-related diseases. Several TCM have been found to show considerable effect in the treatment of gout, including Cortex Phellodendri Amurensis, Radix Achyranthis Bidentatae, Rhizoma Atractylodis Lancea, Rhizoma Smilacis Glabrae, Semen Coicis Albais, Viola yedoensis Makino, Lobelia chinensi Lour, Isatis indigotica Fortune and so on. These TCM share similarities in terms of their components, which usually contain antioxidant and anti-inflammatory materials such as berberine, phellodendrine and magnoflorine. Combinational use of TCM as a formula might improve therapeutic efficacy and minimised adverse effect. In addition, FDA-approved drugs including istradefylline, dipyridamole, suramin, clopidogrel, prasugrel, cangrelor, ticagrelor, etc. are also therapeutic options targeting purine metabolism or purinoceptors