Biology of purinergic signalling: Its ancient evolutionary roots, its omnipresence and its multiple functional significance

Verkhratsky, Alexei; Burnstock, Geoffrey

doi:10.1002/bies.201400024

Cited by 139 publications

(145 citation statements)

References 91 publications

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“…P2 receptors are further divided into ligand-gated ion channel receptors, P2X, and G protein-coupled receptor, P2Y, subfamilies. To date, four P1 receptors (A 1,2a,2b,3 ), seven P2X receptors (P2X [1][2][3][4][5][6][7] ) and eight P2Y receptors (P2Y 1,2,4,6,11-14 ) have been identified in mammalian cells (4). The adenosine receptor subtypes A 1 and A 3 downregulate the production of cAMP, while A 2a and A 2b subtypes up-regulate the production of cAMP.…”

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confidence: 99%

Purinergic Receptor Expression and Cellular Responses to Purinergic Agonists in Human Prostate Cancer Cells

Lertsuwan

Peters

Johnson

et al. 2017

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Extracellular nucleotides were first proposed as signaling molecules in 1972 (1). Signaling through purinergic receptors is ubiquitous due to the diversity of purine and pyrimidine ligands, the number of receptors and extracellular nucleotidases. Purinergic signaling has been shown to play a role in many pathways including neurotransmission (2), cell differentiation, hormone secretion, vasodilation, cell proliferation, wound healing and apoptosis (3). There are two distinct families of purinergic receptors: P1 receptors for adenosine and P2 receptors for ATP/ADP and UTP/UDP ligands. P2 receptors are further divided into ligand-gated ion channel receptors, P2X, and G protein-coupled receptor, P2Y, subfamilies. To date, four P1 receptors (A 1,2a,2b,3 ), seven P2X receptors (P2X 1-7 ) and eight P2Y receptors (P2Y 1,2,4,6,11-14 ) have been identified in mammalian cells (4). The adenosine receptor subtypes A 1 and A 3 downregulate the production of cAMP, while A 2a and A 2b subtypes up-regulate the production of cAMP. Activation of P2X receptors leads to an influx of cations from the extracellular space, while activation of P2Y receptors leads to either an elevation of intracellular Ca 2+ from endoplasmic reticulum stores or down-regulation of cAMP production depending on the specific subtype of P2Y receptor activated.Growth suppression by the P2 agonist, ATP, was demonstrated first by Rapaport in 1983 (5). Exogenous ATP was shown to suppress the growth of pancreatic and colon cancer by causing cell-cycle arrest in S-phase. To date, the anticancer activity of extracellular nucleotides has been investigated in many types of cancer, including leukemia, melanoma and non-melanoma skin cancer, colorectal cancer, lung cancer, cervical cancer, prostate cancer (PCa) and squamous cell skin cancer (6). These led to clinical trials in patients with colorectal and non-small cell lung cancer that showed promising results with limited side-effects (7-9).PCa is the most frequently diagnosed cancer in North American men and the second leading cause of cancerrelated death in American men. It was estimated that there would be approximately 180,890 new cases of PCa and 26,5120 related deaths in the United States alone in 2016 (10). Current standard treatments for advanced PCa include various hormonal therapies whose goal is the ablation of androgens and their action (11). Even though 70% to 80% of patients respond well to first-line treatment, most patients eventually develop castrate-resistant disease (CRPCa) (12). Novel therapy therefore is needed to eliminate both early and 529 Τhis article is freely accessible online.

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Purinergic Receptor Expression and Cellular Responses to Purinergic Agonists in Human Prostate Cancer Cells

Lertsuwan

Peters

Johnson

et al. 2017

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“…Already some prokaryotes are known to release ATP, which could be used for intercellular communications [191], whereas the plasmalemmal channels-mediated ATP release is described in polyphenic fungi, type Candida albicans [192]. Biological effects of extracellular ATP are many, and they are widespread throughout virtually all life forms [190]. In prokaryotes, exposure to ATP affects bacterial growth and development, sporulation and germination, changes ion fluxes and alters gene expression [193 -196].…”

Section: Ca 2þ As a Regulator Of Programmed Cell Deathmentioning

confidence: 99%

Inseparable tandem: evolution chooses ATP and Ca²⁺to control life, death and cellular signalling

Plattner

Verkhratsky

2016

Phil. Trans. R. Soc. B

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From the very dawn of biological evolution, ATP was selected as a multipurpose energy-storing molecule. Metabolism of ATP required intracellular free Ca 2þ to be set at exceedingly low concentrations, which in turn provided the background for the role of Ca 2þ as a universal signalling molecule. The early-eukaryote life forms also evolved functional compartmentalization and vesicle trafficking, which used Ca 2þ as a universal signalling ion; similarly, Ca 2þ is needed for regulation of ciliary and flagellar beat, amoeboid movement, intracellular transport, as well as of numerous metabolic processes. Thus, during evolution, exploitation of atmospheric oxygen and increasingly efficient ATP production via oxidative phosphorylation by bacterial endosymbionts were a first step for the emergence of complex eukaryotic cells. Simultaneously, Ca 2þ started to be exploited for shortrange signalling, despite restrictions by the preset phosphate-based energy metabolism, when both phosphates and Ca 2þ interfere with each other because of the low solubility of calcium phosphates. The need to keep cytosolic Ca 2þ low forced cells to restrict Ca 2þ signals in space and time and to develop energetically favourable Ca 2þ signalling and Ca 2þ microdomains. These steps in tandem dominated further evolution. The ATP molecule (often released by Ca 2þ -regulated exocytosis) rapidly grew to be the universal chemical messenger for intercellular communication; ATP effects are mediated by an extended family of purinoceptors often linked to Ca 2þ signalling. Similar to atmospheric oxygen, Ca 2þ must have been reverted from a deleterious agent to a most useful (intra-and extracellular) signalling molecule. Invention of intracellular trafficking further increased the role for Ca 2þ homeostasis that became critical for regulation of cell survival and cell death. Several mutually interdependent effects of Ca 2þ and ATP have been exploited in evolution, thus turning an originally unholy alliance into a fascinating success story.This article is part of the themed issue 'Evolution brings Ca 2þ and ATP together to control life and death'.

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“…In the context of synaptic physiology, however, ATP plays another fundamental role, being a major neurotransmitter. ATP as a signalling molecule for intercellular communications is unique, being almost ubiquitous: purinergic transmission is present in all living forms, from protists and fungi to plants and animals [16]. In the nervous system, purinergic transmission is similarly ubiquitous without any apparent anatomical segregation that is characteristic for other neurotransmitters (for example, dopamine being present mainly in the midbrain and nigro-striatum and acetylcholine (ACh) in the brainstem, hippocampus and parts of the cortex as well as being the main peripheral neurotransmitter).…”

Section: Atp and Ca 2þ Link Cellular Energetics And Signallingmentioning

confidence: 99%

Calcium and ATP control multiple vital functions

Petersen

Verkhratsky

2016

Phil. Trans. R. Soc. B

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Life on Planet Earth, as we know it, revolves around adenosine triphosphate (ATP) as a universal energy storing molecule. The metabolism of ATP requires a low cytosolic Ca 2+ concentration, and hence tethers these two molecules together. The exceedingly low cytosolic Ca 2+ concentration (which in all life forms is kept around 50–100 nM) forms the basis for a universal intracellular signalling system in which Ca 2+ acts as a second messenger. Maintenance of transmembrane Ca 2+ gradients, in turn, requires ATP-dependent Ca 2+ transport, thus further emphasizing the inseparable links between these two substances. Ca 2+ signalling controls the most fundamental processes in the living organism, from heartbeat and neurotransmission to cell energetics and secretion. The versatility and plasticity of Ca 2+ signalling relies on cell specific Ca 2+ signalling toolkits, remodelling of which underlies adaptive cellular responses. Alterations of these Ca 2+ signalling toolkits lead to aberrant Ca 2+ signalling which is fundamental for the pathophysiology of numerous diseases from acute pancreatitis to neurodegeneration. This paper introduces a theme issue on this topic, which arose from a Royal Society Theo Murphy scientific meeting held in March 2016. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

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Biology of purinergic signalling: Its ancient evolutionary roots, its omnipresence and its multiple functional significance

Cited by 139 publications

References 91 publications

Purinergic Receptor Expression and Cellular Responses to Purinergic Agonists in Human Prostate Cancer Cells

Purinergic Receptor Expression and Cellular Responses to Purinergic Agonists in Human Prostate Cancer Cells

Inseparable tandem: evolution chooses ATP and Ca²⁺to control life, death and cellular signalling

Calcium and ATP control multiple vital functions

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Biology of purinergic signalling: Its ancient evolutionary roots, its omnipresence and its multiple functional significance

Cited by 139 publications

References 91 publications

Purinergic Receptor Expression and Cellular Responses to Purinergic Agonists in Human Prostate Cancer Cells

Purinergic Receptor Expression and Cellular Responses to Purinergic Agonists in Human Prostate Cancer Cells

Inseparable tandem: evolution chooses ATP and Ca2+to control life, death and cellular signalling

Calcium and ATP control multiple vital functions

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Inseparable tandem: evolution chooses ATP and Ca²⁺to control life, death and cellular signalling