Control of neuronal activity by the co-transmitter ATP: Role of P2Y1 receptors

嗅球中嘌呤能递质系统蛋白的显著表达表明该信号通路在气味信息处理中起重要作用。然而，ATP及其代谢物如何影响这一大脑区域的神经元信号尚不清楚。最近，我们的研究小组证明ATP与谷氨酸一起作为共递质通过感觉神经元释放，激活神经胶质细胞。此外，通过笼状核苷酸的光解释放，我们可以首次证明ATP调节嗅球中的神经元信号转导。ATP的光解释放，模拟生理释放，通过P2Y1受体导致神经元网络自发活动的调节。在提议的项目中，ATP对神经元网络的影响将被详细地揭示。功能表达P2Y1受体的神经元将通过结合膜片钳记录和共聚焦钙成像，利用笼中化合物的ATP光解释放来鉴定。我们的初步工作表明，谷氨酸能神经元，如二尖瓣细胞或外部簇状细胞，是气味信息处理所必需的，是ATP的目标。我们的目的是阐明g蛋白偶联P2Y1受体的激活控制神经元兴奋性的细胞和分子机制。此外，我们将研究内源性释放的ATP如何通过电刺激传入（嘌呤能）轴突来刺激这种嘌呤能信号通路。我们期待对嘌呤能系统影响嗅球神经元表现的机制，以及这如何调节气味信息处理的新见解。

The pronounced expression of proteins of the purinergic transmitter system in the olfactory bulb suggests an important role of this signalling pathway in the processing of odour information. Yet, how ATP and its metabolites affect neuronal signalling in this brain region is not known. Recently, our group could demonstrate that ATP is released as co-transmitter together with glutamate by sensory neurons, activating glial cells. Furthermore, by means of photolytic release of caged nucleotides, we could show for the first time that ATP modulates neuronal signal transduction in the olfactory bulb. Photolytic release of ATP, mimicking the physiological release, results in the modulation of spontaneous activity of the neuronal network via P2Y1 receptors. In the proposed project, the impact of ATP on the neuronal network will be unravelled in detail. Neurons that functionally express P2Y1 receptors will be identified using photolytic release of ATP from caged compounds in combination with patch-clamp recordings and confocal calcium imaging. Our preliminary work suggests that glutamatergic neurons such as mitral cells or external tufted cells, which are essential for odour information processing, are the targets of ATP. It is our aim to elucidate the cellular and molecular mechanisms by which the activation of G-protein-coupled P2Y1 receptors controls the excitability of the neurons. In addition, we will study how endogenously released ATP stimulates this purinergic signalling pathway by using electrical stimulation of afferent (purinergic) axons. We expect new insights into the mechanisms by which the purinergic system affects neuronal performance in the olfactory bulb, and how this modulates odour information processing.