ATP- and Adenosine-Mediated Signaling in the Central Nervous System: Preface

Fusao Kato
2004 Journal of Pharmacological Sciences  
Adenine nucleotides and nucleosides, mainly ATP and adenosine, are released into the extracellular milieu and play a wide variety of important roles in cell-to-cell signaling in almost all organs, including the central nervous system (CNS). The targets of adenosine are four types of G-protein-coupled receptors (GPCRs), A 1 , A 2A , A 2B , and A 3 receptors (also called P1 receptors); and ATP activates two distinct receptor types of the P2receptor family: ionotropic P2X receptors and
more » ... ors and metabotropic P2Y receptors. Apparently the story seems quite simple and ordinary: two types of receptors activated by two distinct endogenous agonists. However, recent advances in purinoceptor research have made the story more complicated. The strongest argument is that ATP and adenosine are highly related substances in the living tissue, especially in the brain, not only because the former can be converted to the latter in the extracellular space, but also because their receptor systems are closely related from molecular to local network levels and often share common targets. In this regard, ATP and adenosine, together with their receptors and ectoenzymes that breakdown ATP, form a quite unique regulatory system in the CNS. The review articles presented here introduce recent advances in studies on this coordinated ATP-adenosine systems at diverse levels. The first two articles describe distinct but essential views on the interaction between ATP and adenosine receptors, providing reasonable answers to the long-asked question of an unidentified receptor activated both by ATP and adenosine. Using the advanced technique of bioluminescence resonance energy transfer (BRET), K. Yoshioka and H. Nakata clearly demonstrate the functional heterodimerization of A 1 and P2Y 2 receptors, which is a novel example to add to the growing list of GPCR heterodimers. I. Matsuoka and S. Ohkubo, based on their detailed pharmacological analyses, stress the importance of the spatial configuration of three actors, P1 receptor, P2 receptor, and ecto-nucleotidases, on the membrane which allows ATP to be a potent activator of both P1 and P2 receptors through intermediary of extracellular catabolism. The most exciting subject today in the purinoceptor field is the glia-neuron interaction. T. Nishizaki, who co-chaired the symposium with myself, here demonstrates that activation of A 2A (formerly A 2a ) receptors of the astrocytes with a low concentration of adenosine surprisingly results in vesicular release of glutamate through yet unidentified exocytosis mechanisms. The standpoint introduced by S. Fujii is unique: there are no purinoceptors underlying the effect of ATP. Rather, ATP plays only a side role giving phosphate to the ecto-kinases that phosphorylate the extracellular domain of synaptic proteins, resulting in long-term modification of the synaptic transmission in the hippocampus. F. Kato et al. introduce two examples of local brain networks, where ATP modifies synaptic transmission or neuronal excitability in diametrically opposite directions at distinct synapses of single neurons, through concurrent activation of P1 and P2 receptors, which is largely due to higher activity of ecto-nucleotidases in the brain slices than in isolated cell preparations. Finally, K. Inoue and his colleagues introduce their convincing demonstration that P2X 4 receptors expressed in the microglia play a pivotal role in establishment of the allodynia, a form of chronic neurogenic pain. This is another example of glia-neuron interaction, but moreover, this is a promising model in which a system composed of distinct cell types, as is the case in the native brain tissue, can be a novel target of future purinergic drug therapies. This forum minireview is based on the symposium at
doi:10.1254/jphs.94.87 fatcat:zli2ymhhwjdpbktl2q44efcdmq