Extracellular creatine kinase may modulate purinergic signalling
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REVIEW ARTICLE
Extracellular creatine kinase may modulate purinergic signalling L. M. Brewster 1 Received: 13 December 2019 / Accepted: 2 June 2020 # Springer Nature B.V. 2020
Abstract Extracellular purine nucleotides and nucleosides including ADP and ATP regulate a wide array of physiological processes including platelet aggregation, vasomotor responses and inflammation through specific purinergic receptors. In the recent years, a strong association has been reported between circulating cytoplasmic-type creatine kinase and adverse clinical outcomes such as major bleeding, hypertension and obesity. Therefore, it is proposed that extracellular CK may modulate purinergic signalling through its ADP binding and/or ATP-generating effect. Keywords Creatine kinase . ADP . ATP . Purinergic signalling . ADP-dependent platelet aggregation . Hypertension
Introduction Extracellular nucleotides and nucleosides originating through lytic and non-lytic processes from blood cells, the vessel wall, nerves and tissues may act as short-term or long-term signalling molecules via specific purinergic receptors, to regulate a wide array of physiological functions including neurotransmission, platelet aggregation, vasomotor responses, inflammation and trophic responses. The large body of evidence on this signalling system has been exquisitely reviewed by several authors [1–6]. In brief, this highly conserved signalling system governs a functional step-wise interaction between extracellular purines and an interconnected network of ectoenzymes that may generate as well as degrade purine and pyrimidine nucleotides and nucleosides, to provide tight control over the duration and the magnitude of the responses. Specific ligand-gated ionotropic purine P2X receptors (subtypes P2X1–7) are activated by ATP, while G protein coupled metabotropic P2Y receptors have main ligand preferences in the purine molecules ADP (P2Y1); UTP, ATP (P2Y2); UTP (P2Y4); UDP (P2Y6); ATP, NAD+ (P2Y11); ADP (P2Y12 and P2Y13) and UDP (P2Y14). Finally, the G protein-coupled receptor P1, with subtypes A1, A2A, A2B and A3, binds adenosine [1–6] and potentially AMP (subtype A 1 ) [7]. The
* L. M. Brewster [email protected] 1
CK Science Foundation, POB 23639, 1100, EC Amsterdam, the Netherlands
interconversion of these purinergic agonists is catalysed by different enzyme families, ecto-nucleoside triphosphate diphosphohydrolases that hydrolyse nucleoside tri- and diphosphates into nucleoside monophosphates, ecto-5′-nucleotidase that converts AMP to adenosine, ecto-adenosine deaminase that converts adenosine into inosine, and nucleotidases that hydrolyse other substrates aside nucleoside tri-, di-, and monophosphates. The ectonucleotide pyrophosphatase/ phosphodiesterase family also hydrolyses dinucleoside polyphosphates, ADP ribose and other substrates, but not AMP, while alkaline phosphatases also degrade other phosphate monoesters [1–5]. More recently, ATP-generating enzymes appeared to be relevant for extracellular purine signalling, including Ecto-F1FoATP synthase
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