The Library

The novel NTPDase inhibitor sodium polyoxotungstate (POM-1) inhibits ATP breakdown but also blocks central synaptic transmission, an action independent of NTPDase inhibition

Tools

Wall, M. (Mark), Wigmore, Geoffery, Lopatář, Ján, Frenguelli, Bruno G. and Dale, Nicholas. (2008) The novel NTPDase inhibitor sodium polyoxotungstate (POM-1) inhibits ATP breakdown but also blocks central synaptic transmission, an action independent of NTPDase inhibition. Neuropharmacology, Vol.55 (No.7). pp. 1251-1258. ISSN 0028-3908

Full text not available from this repository.

Official URL: http://dx.doi.org/10.1016/j.neuropharm.2008.08.005

Abstract

Understanding the mechanisms and properties of purinergic signalling would be greatly assisted by the discovery of subtype selective and potent inhibitors of the NTPDase enzymes, which metabolise nucleotides such as ATP and ADP in the extracellular space. Currently ARL 67156 is the best available NTPDase inhibitor, but its relatively poor efficacy means that negative results are difficult to interpret. POM-1 (sodium polyoxotungstate) is a novel NTPDase inhibitor, which has shown promising results with the inhibition of recombinant NTPDases 1, 2 and 3. We have tested the effectiveness and physiological effects of POM-1 with cerebellar and hippocampal slices. Using the malachite green phosphate assay, HPLC and biosensor measurements we have found that POM-1 is more effective at blocking ATP breakdown in cerebellar slices than ARL 67156. The site of inhibition is at the first step of the breakdown cascade (conversion of ATP to ADP) and the effects of POM-1 appear readily reversible. However, POM-1 has multiple effects on synaptic transmission. At the cerebellar parallel fibre-Purkinje cell (PF) synapse POM-1 produced a long lasting inhibition of transmission, which was preceded in a minority of synapses by a transient increase in PF excitatory postsynaptic potential (EPSP) amplitude (similar to 20%). This increase in PF EPSP amplitude appears to result from a reduction in the tonic activation of presynaptic A, receptors, consistent with POM-1 preventing the breakdown of ATP to adenosine. The reduction in PF EPSP amplitude does not however appear to result from NTPDase inhibition as it persists when both adenosine and ATP (P2Y and P2X) receptors are blocked. An increase in paired pulse ratio and a reduction in presynaptic volley amplitude suggest that there is a presynaptic component of POM-1 action which reduces glutamate release. POM-1 produced similar inhibition at climbing fibre synapses and at hippocampal CA1 pyramidal synapses. Thus although POM-1 is more effective than ARL 67156 at blocking ATP breakdown its usefulness is limited by off-target actions on synaptic transmission. (C) 2008 Elsevier Ltd. All rights reserved.

Item Type:

Journal Article

Subjects:

Q Science > QP Physiology
R Medicine > RS Pharmacy and materia medica

Divisions:

Faculty of Science > Life Sciences (2010- )

Library of Congress Subject Headings (LCSH):

Enzyme inhibitors, Adenosine triphosphatase, Neural transmission, Cerebellum, Hippocampus (Brain), Biosensors

Journal or Publication Title:

Neuropharmacology

Publisher:

Pergamon

ISSN:

0028-3908

Official Date:

December 2008

Dates:

Date	Event
December 2008	Published

Volume:

Vol.55

Number:

No.7

Number of Pages:

Page Range:

pp. 1251-1258

Identification Number:

10.1016/j.neuropharm.2008.08.005

Status:

Peer Reviewed

Publication Status:

Published

Access rights to Published version:

Restricted or Subscription Access

Funder:

Epilepsy Research UK

References:

Ackland, G.L., Kasymov, V., Gourine, A.V., 2007. Physiological and pathophysiological
roles of extracellular ATP in chemosensory control of breathing. Biochemical
Society Transactions 35, 1264–1268.
Anderson, W.W., Collingridge, G.L., 2001. The LTP Program: a data acquisition
program for on-line analysis of long-term potentiation and other synaptic
events. Journal of Neuroscience Methods 108, 71–83.
Armstrong, J.N., Brust, T.B., Lewis, R.G., MacVicar, B.A., 2002. Activation of presynaptic
P2X7-like receptors depresses mossy fiber-CA3 synaptic transmission through
p38 mitogen-activated protein kinase. Journal of Neuroscience 22, 5938–5945.
Burnstock, G., 2007a. Physiology and pathophysiology of purinergic neurotransmission.
Physiological Reviews 87, 659–797.
Burnstock, G., 2007b. Purine and pyrimidine receptors. Cellular and Molecular Life
Sciences 64 (147), 1–83.
Carter, S.G., Karl, D.W., 1982. Inorganic phosphate assay with malachite green: an
improvement and evaluation. Journal of Biochemical and Biophysical Methods
7, 7–13.
Dale, N., Pearson, T., Frenguelli, B.G., 2000. Direct measurement of adenosine
release during hypoxia in the CA1 region of the rat hippocampal slice. Journal of
Physiology 526, 143–155.
Dittman, J.S., Regehr, W.G., 1996. Contributions of calcium-dependent and calciumindependent
mechanisms to presynaptic inhibition at a cerebellar synapse.
Journal of Neuroscience 16, 1623–1633.
Dunwiddie, T.V., Miller, K.K., 1993. Effects of adenosine and cadmium on presynaptic
fiber spikes in the CA1 region of rat hippocampus in vitro. Neuropharmacology
32, 1061–1068.
Etherington, L.A., Frenguelli, B.G., 2004. Endogenous adenosine modulates epileptiform
activity in rat hippocampus in a receptor subtype-dependent manner.
European Journal of Neuroscience 19, 2539–2550.
Fredholm, B.B., Arslan, G., Halldner, L., Kull, N., Shulte, G., Wasserman, W., 2000.
Structure and function of adenosine receptors and their genes. Naunyn
Schmeidebers Archives of Pharmacology 362, 364–374.
Frenguelli, B.G., Wigmore, G., Llaudet, E., Dale, N., 2007. Temporal and mechanistic
dissociation of ATP and adenosine release during ischaemia in the mammalian
hippocampus. Journal of Neurochemistry 101, 1400–1413.
Grenz, A., Zhang, H., Hermes, M., Eckle, T., Klingel, K., Huang, D.Y., Mu¨ ller, C.E.,
Robson, S.C., Osswald, H., Eltzschig, H.K., 2007. Contribution of E-NTPDase1
(CD39) to renal protection from ischemia-reperfusion injury. The Federation of
American Societies for Experimental Biology Journal 21, 2863–2873.
Hashimoto, K., Kano, M., 1998. Presynaptic origin of paired-pulse depression at
climbing fibre-Purkinje cell synapses in the rat cerebellum. Journal of Physiology
506, 391–405.
Khakh, B.S., 2001. Molecular physiology of P2X receptors and ATP signalling at
synapses. Nature Reviews Neuroscience 2, 165–174.
Kocsis, J.D., Eng, D.L., Bhisitkul, R.B., 1984. Adenosine selectively blocks parallelfiber-
mediated synaptic potentials in rat cerebellar cortex. Proceedings of the
National Academy of Science 81, 6531–6534.
Ko¨ hler, D., Eckle, T., Faigle, M., Grenz, A., Mittelbronn, M., Laucher, S., Hart, M.L.,
Robson, S.C., Mu¨ ller, C.E., Eltzschig, H.K., 2007. CD39/ectonucleoside triphosphate
diphosphohydrolase 1 provides myocardial protection during cardiac
ischemia/reperfusion injury. Circulation 116, 1784–1794.
Latini, S., Pedata, F., 2001. Adenosine in the central nervous system: release
mechanisms and extracellular concentrations. Journal of Neurochemistry 79,
463–484.
Leon, D., Hervas, C., Miras-Portugal, M.T., 2006. P2Y1 and P2X7 receptors induce
calcium/calmodulin-dependent protein kinase II phosphorylation in cerebellar
granule neurons. European Journal of Neuroscience 23, 2999–3013.
Llaudet, E., Botting, N., Crayston, J., Dale, N., 2003. A three enzyme microelectrode
sensor for detecting purine release from central nervous system. Biosensors and
Bioelectronics 18, 43–52.
Llaudet, E., Hatz, S., Droniou, M., Dale, N., 2005. Microelectrode biosensor for real-time
measurement of ATP in biological tissue. Analytical Chemistry 77, 3267–3273.
Mendoza-Ferna´ ndez, V., Andrew, R.D., Barajas-Lo´ pez, C., 2000. ATP inhibits glutamate
synaptic release by acting at P2Y receptors in pyramidal neurons of
hippocampal slices. Journal of Pharmacology and Experimental Therapeutics
293, 172–179.
Mu¨ ller, C.E., Iqbal, J., Baqi, Y., Zimmermann, H., Ro¨ llich, A., Stephan, H., 2006.
Polyoxometalates – a new class of potent ecto-nucleoside triphosphate
diphosphohydrolase (NTPDase) inhibitors. Bioorganic and Medicinal Chemistry
Letters 16, 5943–5947.
Pearson, T., Nuritova, F., Caldwell, D., Dale, N., Frenguelli, B.G., 2001. A depletable
pool of adenosine in area CA1 of the rat hippocampus. Journal of Neuroscience
21, 2298–2307.
Rudolphi, K.A., Schubert, P., Parkinson, F.E., Fredholm, B.B., 1992. Neuroprotective
role of adenosine in cerebral ischemia. Trends in Pharmacological Sciences 13,
439–445.
Schwarzschild, M.A., Agnati, L., Fuxe, K., Chen, J.F., Morelli, M., 2006. Targeting
adenosine A2A receptors in Parkinson’s disease. Trends in Neuroscience 29,
647–654.
Takahashi, M., Kovalchuk, Y., Attwell, D., 1995. Pre- and postsynaptic determinants
of EPSC waveform at cerebellar fiber and parallel fiber to Purkinje cell synapses.
Journal of Neuroscience 15, 5693–5702.
Wall, M.J., Dale, N., 2007. Auto inhibition of rat parallel fibre-Purkinje cell synapses
by activity-dependent adenosine release. Journal of Physiology 581, 553–565.
Wall, M.J., Atterbury, A., Dale, N., 2007. Control of basal extracellular adenosine
concentration in rat cerebellum. Journal of Physiology 582, 137–151.
Yuan, Y., Atchison, W.D., 1999. Comparative effects of methylmercury on parallelfiber
and climbing fiber responses of rat cerebellar slices. Journal of
Pharmacology and Experimental Therapeutics 288, 1015–1025.
Zimmermann, H., 2000. Extracellular metabolism of ATP and other nucleotides.
Naunyn-Schmeidebergs Archives of Pharmacology 362, 299–309.
Zimmermann, H., 2006. Nucleotide signalling in nervous system development.
Pflugers Archives 452, 573–588.