Purinergic Signalling: Therapeutic Developments

Abstract

Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

Pannexin‐1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration

“…1 Our knowledge about the mechanisms leading to the release of nucleotides is less settled. Extracellular nucleosides and nucleo tides exert their action via a number of purinergic receptors (Adenosine, P2X and P2Y), which are well characterized in many cells, and provide attractive therapeutic targets, for example, in neurologic and cardiovascular diseases, inflam mation, osteoporosis, cancer and diabetes.…”

“…Extracellular nucleosides and nucleo tides exert their action via a number of purinergic receptors (Adenosine, P2X and P2Y), which are well characterized in many cells, and provide attractive therapeutic targets, for example, in neurologic and cardiovascular diseases, inflam mation, osteoporosis, cancer and diabetes. 1 Our knowledge about the mechanisms leading to the release of nucleotides is less settled. Nevertheless, it is known that most cells have a basal 'resting' ATP release 2 and, depending on the cell type, ATP release can be also stimulated by hormones, agonists, changes in membrane voltage, mechanical and chemical stress.…”

Involvement of purinergic 2X4 receptor in glycoprotein 120‐induced pyroptosis in dorsal root ganglia

“…A large amount of extracellular ATP released from nerve injury can initiate an inflammatory cascade (Burnstock ; Surprenant and North ; Suurväli et al, ; Burnstock ). P2X 4 may trigger inflammation in response to high ATP release (Burnstock ; Suurväli et al, ; Burnstock ). Our data indicated that the P2X 4 agonist (ATP) enhanced gp120‐induced injury in SGCs.…”

Probing structure-activity relationship in β-arrestin2 recruitment of diversely substituted adenosine derivatives

“…The human A 3 AR (hA 3 AR) is highly expressed in lung, liver and immune cells, with lower expression levels in the heart, brain and eye [4]. In recent years, the A 3 AR has attracted interest as a therapeutic target due to its role in the pathogenesis of heart and vascular diseases, autoimmune inflammatory disorders, COPD and asthma, along with different types of cancer [5–8]. A 3 AR expression is upregulated in various tumour cells, modulating tumour growth depending on the tumour type, the other AR subtypes present, the surrounding immune cells and micro-environmental conditions involved [9, 10].…”