Purinergic signalling: past, present and future

The discovery of non-adrenergic, non-cholinergic neurotransmission in the gut and bladder in the early 1960's is described as well as the identification of adenosine 5'-triphosphate (ATP) as a transmitter in these nerves in the early 1970's. The concept of purinergic cotransmission was formulated in 1976 and it is now recognized that ATP is a cotransmitter in all nerves in the peripheral and central nervous systems. Two families of receptors to purines were recognized in 1978, P1 ( adenosine) receptors and P2 receptors sensitive to ATP and adenosine diphosphate ( ADP). Cloning of these receptors in the early 1990's was a turning point in the acceptance of the purinergic signalling hypothesis and there are currently 4 subtypes of P1 receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of G protein-coupled receptors. Both short-term purinergic signalling in neurotransmission, neuromodulation and neurosecretion and long-term ( trophic) purinergic signalling of cell proliferation, differentiation, motility, death in development and regeneration are recognized. There is now much known about the mechanisms underlying ATP release and extracellular breakdown by ecto-nucleotidases. The recent emphasis on purinergic neuropathology is discussed, including changes in purinergic cotransmission in development and ageing and in bladder diseases and hypertension. The involvement of neuron-glial cell interactions in various diseases of the central nervous system, including neuropathic pain, trauma and ischemia, neurodegenerative diseases, neuropsychiatric disorders and epilepsy are also considered

Purinergic signaling in the gastrointestinal tract

Geoffrey Burnstock completed a BSc at King's College London and a PhD at University College London. He held postdoctoral fellowships with Wilhelm Feldberg (National Institute for Medical Research), Edith Bülbring (University of Oxford) and C. Ladd Prosser (University of Illinois). He was appointed to a Senior Lectureship in Melbourne University in 1959 and became Professor and Chairman of Zoology in 1964. In 1975 he became Head of Department of Anatomy and Developmental Biology at UCL and Convenor of the Center of Neuroscience. He has been Director of the Autonomic Neuroscience Institute at the Royal Free Hospital School of Medicine since 1997. He was elected to the Australian Academy of Sciences in 1971, the Royal Society in 1986, the Academy of Medical Sciences in 1998 and an Honorary Fellow of the Royal College of Surgeons and the Royal College of Physicians in 1999 and 2000. He was awarded the Royal Society Gold Medal in 2000. He is editor-in-chief of the journals Autonomic Neuroscience and Purinergic Signalling and on the editorial boards of many other journals. Geoffrey Burnstock's major research interest has been autonomic neurotransmission and he is best known for his seminal discovery of purinergic transmission and receptors, their signaling pathways and functional relevance. He has supervised over 100 PhD and MD students and published over 1400 original papers, re-views and books. He was first in the Institute of Scientific Information list of most cited scientists in Pharmacology and Toxicology from 1994-2004 [59.083 citations (March 2011) and an h-index of 109]

Purinergic mechanosensory transduction and visceral pain

In this review, evidence is presented to support the hypothesis that mechanosensory transduction occurs in tubes and sacs and can initiate visceral pain. Experimental evidence for this mechanism in urinary bladder, ureter, gut, lung, uterus, tooth-pulp and tongue is reviewed. Potential therapeutic strategies are considered for the treatment of visceral pain in such conditions as renal colic, interstitial cystitis and inflammatory bowel disease by agents that interfere with mechanosensory transduction in the organs considered, including P2X(3) and P2X(2/3) receptor antagonists that are orally bioavailable and stable in vivo and agents that inhibit or enhance ATP release and breakdown

Dual control of vascular tone and remodelling by ATP released from nerves and endothelial cells

Purinergic signalling is important both in short-term control of vascular tone and in longer-term control of cell proliferation, migration and death involved in vascular remodelling. There is dual control of vascular tone by ATP released from perivascular nerves and by ATP released from endothelial cells in response to changes in blood flow (shear stress) and hypoxia. Both ATP and its breakdown product, adenosine, regulate smooth muscle and endothelial cell proliferation. The involvement of these regulatory mechanisms in pathological conditions, including hypertension, atherosclerosis, restenosis, diabetes and vascular pain, are discussed

Short- and long-term (trophic) purinergic signalling

There is long-term (trophic) purinergic signalling involving cell proliferation, differentiation, motility and death in the development and regeneration of most systems of the body, in addition to fast purinergic signalling in neurotransmission, neuromodulation and secretion. It is not always easy to distinguish between short- and long-term signalling. For example, adenosine triphosphate (ATP) can sometimes act as a short-term trigger for long-term trophic events that become evident days or even weeks after the original challenge. Examples of short-term purinergic signalling during sympathetic, parasympathetic and enteric neuromuscular transmission and in synaptic transmission in ganglia and in the central nervous system are described, as well as in neuromodulation and secretion. Long-term trophic signalling is described in the immune/defence system, stratified epithelia in visceral organs and skin, embryological development, bone formation and resorption and in cancer. It is likely that the increase in intracellular Ca(2+) in response to both P2X and P2Y purinoceptor activation participates in many short- and long-term physiological effects.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'

Purinergic Signalling and Neurological Diseases: An Update

Purinergic signalling, i.e. ATP as an extracellular signalling molecule and cotransmitter in both peripheral and central neurons, is involved in the physiology of neurotransmission and neuromodulation. Receptors for purines have been cloned and characterised, including 4 subtypes of the P1(adenosine) receptor family, 7 subtypes of the P2X ion channel nucleotide receptor family and 8 subtypes of the P2Y G protein-coupled nucleotide receptor family. The roles of purinergic signalling in diseases of the central nervous system and the potential use of purinergic compounds for their treatment are attracting increasing attention. In this review, the focus is on the findings reported in recent papers and reviews to update knowledge in this field about the involvement of purinergic signalling in Alzheimer’s, Parkinson’s and Huntington’s diseases, multiple sclerosis, amyotrophic lateral sclerosis, degeneration and regeneration after brain injury, stroke, ischaemia, inflammation, migraine, epilepsy, psychiatric disorders, schizophrenia, bipolar disorder, autism, addiction, sleep disorders and brain tumours. The use in particular of P2X7 receptor antagonists for the treatment of neurodegenerative diseases, cancer, depression, stroke and ischaemia, A2A receptor antagonists for Parkinson’s disease and agonists for brain injury and depression and P2X3 receptor antagonists for migraine and seizures has been recommended. P2Y receptors have also been claimed to be involved in some central nervous disorders

Sympathetic innervation of the kidney in health and disease: Emphasis on the role of purinergic cotransmission

There is introductory information about non-synaptic transmission at sympathetic neuroeffector junctions and sympathetic nerve cotransmission utilizing noradrenaline and ATP as cotransmitters. Then the organzation and location of sympathetic nerves in different sites in the kidney are described, including renal arteries, juxtaglomerular arterioles and renal tubules. Sympathetic nervous control of glomerular filtration rate and of renin secretion are discussed. Evidence, obtained largely from experiments on animals, for sympathetic nerve modulation of the transport of water, sodium and other ions in the collecting duct of the nephron is described. Finally, there is coverage of the roles of sympathetic nerves in renal diseases, including hypertension, diabetes, hypothyroidism and ischaemia

The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed

CYTOPLASMIC FILAMENTS IN DEVELOPING AND ADULT VERTEBRATE SMOOTH MUSCLE

An extensive study of adult and developing smooth muscle has revealed the widespread occurrence of a distinct filament with an average diameter of about 100 A (termed the 100 A filament). Unlike that of myofilaments, their appearance in longitudinal section is uniform, but in transverse section they have a round profile, occasionally exhibiting a less electron-opaque core. The 100 A filaments are almost invariably preserved under a variety of fixation procedures, whereas myofilaments, particularly the thicker filaments, are preserved inconsistently. The 100 A filaments appear to be randomly oriented throughout the cytoplasm, either singly or in small groups, although they are sometimes concentrated in the juxtanuclear region of the smooth muscle cells. The intimate association of 100 A filaments with dark bodies, in both developing and adult smooth muscle cells, may indicate that these filaments either play a role in dark body formation or, at least, constitute a part of the dark body. The 100 A filaments are conspicuous in developing smooth muscle cells and occasionally form networks or clusters; they appear to decrease in relative number as maturation proceeds, but considerable numbers are still present in adult tissue