Melnik Sergei, Wright Michael, Tanner Julian A, Tsintsadze Timur, Tsintsadze Vera, Miller Andrew D, Lozovaya Natalia
Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine, Russia.
J Pharmacol Exp Ther. 2006 Aug;318(2):579-88. doi: 10.1124/jpet.105.097642. Epub 2006 May 18.
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-[beta,beta'-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 alpha,beta-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.
此前，我们已经描述了二腺苷多磷酸Ap4A和Ap5A对大鼠海马切片中由突触前受体介导的突触传递的调节作用（Klishin等人，1994年）。相比之下，我们现在描述了低微摩尔浓度的不可水解的Ap4A类似物二腺苷-5',5'''-P1,P4-[β,β'-亚甲基]四磷酸（AppCH2ppA）如何对正向诱发的场电位（OFP）产生强烈的非脱敏抑制作用，而不影响兴奋性突触后电流的幅度和逆向诱发的场电位，这是在海马CA1区记录到的。AppCH2ppA对OFP的作用可被P2受体拮抗剂磷酸吡哆醛-6-偶氮苯基-2',4'-二磺酸（PPADS）消除，但嘌呤受体激动剂α,β-亚甲基-ATP和腺苷5'-O-(3-硫代)-三磷酸不能模拟其作用，这表明涉及一种类P2受体，但不属于传统的P2X/P2Y受体类别。二腺苷多磷酸受体（P4）拮抗剂Ip4I（二肌苷四磷酸）无法调节AppCH2ppA的作用。因此，AppCH2ppA的PPADS敏感类P2受体似乎选择性地控制CA1神经元的树突状兴奋。特定的一氧化氮（NO）清除剂2-苯基-4,4,5,5-四甲基-咪唑啉-1-氧基-3-氧化物被证明能显著减弱AppCH2ppA介导的抑制作用，表明NO参与了由AppCH2ppA引发的一系列事件。还证明了腺苷A1受体在更下游的介导作用。因此，AppCH2ppA介导的作用涉及PPADS敏感类P2受体的激活，导致NO的产生，进而刺激细胞内腺苷的合成，继而引起突触后A1受体的激活和随后的突触后CA1树突状抑制。这种空间选择性的突触后树突状抑制可能影响锥体神经元中的树突电活动，并因此介导对神经网络活动的控制。
