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NEUROPHARMACOLOGY

Diadenosine Polyphosphate Analog Controls Postsynaptic Excitation in CA3-CA1 Synapses via a Nitric Oxide-Dependent Mechanism

Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine, Russia (S.M., T.T., V.T., N.L.); and Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, South Kensington, London, United Kingdom (M.W., J.A.T., A.D.M.)

Previously, we have described the modulatory effect of diadenosine polyphosphates Ap₄A and Ap₅A on synaptic transmission in the rat hippocampal slices mediated by presynaptic receptors (Klishin et al., 1994). In contrast, we now describe how nonhydrolyzable Ap₄A analog diadenosine-5',5'''-P¹,P⁴-[,'-methylene]tetraphosphate (AppCH₂ppA) at low micromolar concentrations exerts strong nondesensitizing inhibition of orthodromically evoked field potentials (OFPs) without affecting the amplitude of excitatory postsynaptic currents and antidromically evoked field potentials, as recorded in hippocampal CA1 zone. The effects of AppCH₂ppA on OFPs are eliminated by a P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) but not mimicked by purinoceptor agonists ,-methylene-ATP and adenosine 5'-O-(3-thio)-triphosphate, indicating that a P2-like receptor is involved but not one belonging to the conventional P2X/P2Y receptor classes. Diadenosine polyphosphate receptor (P4) antagonist Ip₄I (diinosine tetraphosphate) was unable to modulate AppCH₂ppA effects. Thus, the PPADS-sensitive P2-like receptor for AppCH₂ppA seems to control selectively dendritic excitation of the CA1 neurons. The specific nitric oxide (NO)-scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide is shown to significantly attenuate AppCH₂ppA-mediated inhibitory effects, indicating that NO is involved in the cascade of events initiated by AppCH₂ppA. Further downstream mediation by adenosine A1 receptors is also demonstrated. Hence, AppCH₂ppA-mediated effects involve PPADS-sensitive P2-like receptor activation leading to the production of NO that stimulates intracellular synthesis of adenosine, causing in turn postsynaptic A1 receptor activation and subsequent postsynaptic CA1 dendritic inhibition. Such spatially selective postsynaptic dendritic inhibition may influence dendritic electrogenesis in pyramidal neurons and consequently mediate control of neuronal network activity.

Address correspondence to: Dr. Natalia Lozovaya, Department of Cellular Membranology, Bogomoletz Institute of Physiology, Bogomoletz str. 4, Kiev, 01024, Ukraine. E-mail: nl{at}serv.biph.kiev.ua