Abstract
Using a patch-clamp technique under voltage clamp conditions, we studied the effect of a non-hydrolyzable analog of diadenosine polyphosphates (AppCH2ppAs) on chemoactivated transmembrane currents through NMDA channels (NMDA currents) in isolated pyramidal neurons of the rat hippocampal CA3 zone. In 55.7% of the cases, AppCH2ppAs caused an increase in the peak amplitude of the currents induced by application of aspartate. In 39.5% of the cases, the agent exerted no effect, while in 4.8% these currents were suppressed. When studying the pharmacological effect of an increase in the amplitude of NMDA currents, we found that potentiation of these currents is mediated, first of all, by activation of P2 purinoceptors and is prevented by a blocker of tyrosine kinases, genistein. Receptor-channel NMDA complexes, due to their ability to be blocked by divalent cations, also contribute to the above effect of AppCH2ppA. Based on the data obtained, we conclude that AppCH2ppA influences NMDA receptors via activation of the P2 receptors and subsequent activation of tyrosine kinases; this leads to the modification of receptor-channel NMDA complexes and to the removal of their tonic blocking by zinc ions.
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References
A. Klishin, N. Lozovaya, and O. Krishtal, “A1 adenosine receptors differentially regulate the N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated components of hippocampal excitatory postsynaptic current in a Ca2+/Mg2+-dependent manner,” Neuroscience, 65, No. 4, 947–953 (1995).
J. Pintor, M. Diaz-Hernandez, J. Gualix, et al., “Diadenosine polyphosphate receptors from rat and guinea-pig brain to human nervous system,” Pharmacol. Ther., 87, Nos. 2/3, 103–115 (2000).
F. Rodriguez-Pascual, R. Cortes, M. Torres, et al., “Distribution of [3H]diadenosine tetraphosphate binding sites in rat brain,” Neuroscience, 77, No. 1, 247–255 (1997).
A. G. McLennan, “Dinucleoside polyphosphates — friend or foe?” Pharmacol. Ther., 87, Nos. 2/3, 73–89 (2000).
M. Wright, J. A. Tanner, and A. D. Miller, “Quantitative single-step purification of dinucleoside polyphosphates,” Anal. Biochem., 316, No. 1, 135–138 (2003).
S. Melnik, M. Wright, J. A. Tanner, et al., “Modulation of synaptic activity in CA3-CA1 by diadenosine polyphosphate analogue,” Neuroscience: Theor. Pract. Aspects, 1, No. 1, 73–74 (2006).
J. A. Tanner, A. Abowath, and A. D. Miller, “Isothermal titration calorimetry reveals a zinc ion as an atomic switch in the diadenosine polyphosphates,” J. Biol. Chem., 277, No. 5, 3073–3078 (2002).
M. P. Cuajungco and G. J. Lees, “Zinc metabolism in the brain: relevance to human neurodegenerative disorders,” Neurobiol. Dis., 4, Nos. 3/4, 137–169 (1997).
F. Zheng, M. B. Gingrich, S. F. Traynelis, et al., “Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition,” Nat. Neurosci., 1, No. 3, 185–191 (1998).
T. Akiyama, J. Ishida, S. Nakagawa, et al., “Genistein, a specific inhibitor of tyrosine-specific protein kinases,” J. Biol. Chem., 262, No. 12, 5592–5595 (1987).
M. Ahlander, I. Misane, P. A. Schott, et al., “A behavioral analysis of the spatial learning deficit induced by the NMDA receptor antagonist MK-801 (dizocilpine) in the rat,” Neuropsychopharmacology, 21, No. 3, 414–426 (1999).
J. A. Gorter and J. P. de Bruin, “Chronic neonatal MK-801 treatment results in an impairment of spatial learning in the adult rat,” Brain Res., 580, Nos. 1/2, 12–17 (1992).
I. Q. Whishaw and R. N. Auer, “Immediate and long-lasting effects of MK-801 on motor activity, spatial navigation in a swimming pool and EEG in the rat,” Psychopharmacology, 98, No. 4, 500–507 (1989).
C. G. Parsons, W. Danysz, and G. Quack, “Glutamate in CNS disorders as a target for drug development: an update,” Drug News Perspect., 11, No. 9, 523–569 (1998).
G. Burnstock, T. Cocks, L. Kasakov, et al., “Direct evidence for ATP release from non-adrenergic, non-cholinergic (’purinergic’) nerves in the guinea-pig taenia coli and bladder,” Eur. J. Pharmacol., 49, No. 2, 145–149 (1978).
G. Collo, R. A. North, E. Kawashima, et al., “Cloning of P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATP-gated ion channels,” J. Neurosci., 16, No. 8, 2495–2507 (1996).
B. S. Khakh, W. R. Proctor, T. V. Dunwiddie, et al., “Allosteric control of gating and kinetics at P2X(4) receptor channels,” J. Neurosci., 19, No. 17, 7289–7299 (1999).
X. Bo, Y. Zhang, M. Nassar, et al., “A P2X purinoceptor cDNA conferring a novel pharmacological profile,” FEBS Lett., 375, Nos. 1/2, 129–133 (1995).
Y. D. Bogdanov, S. S. Wildman, M. P. Clements, et al., “Molecular cloning and characterization of rat P2Y4 nucleotide receptor,” Br. J. Pharmacol., 124, No. 3, 428–430 (1998).
D. Communi, B. Robaye, and J. M. Boeynaems, “Pharmacological characterization of the human P2Y11 receptor,” Br. J. Pharmacol., 128, No. 6, 1199–1206 (1999).
M. Glanzel, R. Bultmann, K. Starke, et al., “Constitutional isomers of Reactive Blue 2-selective P2Y-receptor antagonists?” Eur. J. Med. Chem., 38, No. 3, 303–312 (2003).
J. B. Schachter, Q. Li, J. L. Boyer, et al., “Second messenger cascade specificity and pharmacological selectivity of the human P2Y1-purinoceptor,” Br. J. Pharmacol., 118, No. 1, 167–173 (1996).
J. Simon, T. E. Webb, B. F. King, et al., “Characterization of a recombinant P2Y purinoceptor, ” Eur. J. Pharmacol., 291, No. 3, 281–289 (1995).
F. M. Haug, “Electron microscopical localization of the zinc in hippocampal mossy fiber synapses by a modified sulfide silver procedure,” Histochemie, 8, No. 4, 355–368 (1967).
S. Y. Assaf and S. H. Chung, “Release of endogenous Zn2+ from brain tissue during activity, ” Nature, 308, No. 5961, 734–736 (1984).
M. L. Mayer and G. L. Westbrook, “Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurons,” J. Physiol., 394, 501–527 (1987).
S. Laurberg and J. Zimmer, “Lesion-induced sprouting of hippocampal mossy fiber collaterals to the fascia dentata in developing and adult rats,” J. Comp. Neurol., 200, No. 3, 433–459 (1981).
E. H. Buhl, T. S. Otis, and I. Mody, “Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model,” Science, 271, No. 5247, 369–373 (1996).
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Neirofiziologiya/Neurophysiology, Vol. 38, No. 3, pp. 205–210, May–June, 2006.
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Tsintsadze, V.P., Fedorenko, A.L., Tsintsadze, T.S. et al. Effect of a non-hydrolyzable analog of diadenosine polyphosphates on NMDA-mediated currents in isolated pyramidal neurons of the rat hippocampus. Neurophysiology 38, 169–174 (2006). https://doi.org/10.1007/s11062-006-0041-y
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DOI: https://doi.org/10.1007/s11062-006-0041-y