Investigations into ASIC1a-dependent neuronal death

酸感应离子通道 1a (ASIC1a) 对于正常大脑功能至关重要，但会引发神经元死亡 并导致缺血性脑损伤。细胞外pH值的长期降低伴随着缺血和 ASIC1a 抑制可限制神经损伤。然而，ASIC 在正常生理和功能中也发挥着重要作用。 已建立的 ASIC 诱导的细胞死亡模型使得开发特异性抑制的策略变得困难 ASIC1a 毒性。我们的初步数据支持 ASIC1a 诱导的细胞死亡的新模型。具体来说，我们 发现 ASIC1a 的毒性作用可以通过修饰 ASIC1a 的细胞内区域来消除 δ阿片受体（DOR）的通道或激活。其中一个特别具有挑衅性的方面 研究结果表明，在不降低 ASIC1a 电流的情况下，酸毒性受到抑制，从而表明 该通道的毒性作用和生理作用可以分开。我们的中心假设是 DOR 可以防止 通过信号级联产生酸毒性，信号级联作用于 ASIC1a 的胞内结构域以限制蛋白质 毒性所需的相互作用。为了检验这个假设，我们将定义控制 DOR 作用的机制 ASIC1a 并阐明它们在体内缺血性损伤中的作用。拟议工作的结果将揭示 控制 ASIC1a 诱导毒性的新调节机制，建议新的干预措施来减轻 使用现有的 DOR 激动剂进行 ASIC 诱导的死亡，并揭示了分离生理和死亡的策略 ASIC1a 的病理作用。这些结果将意义重大，因为它们预计将具有广泛的影响 对预防缺血性中风以及其他疾病后脑损伤的影响 神经元酸毒性发挥作用。

The acid sensing ion channel1a (ASIC1a) is essential for normal brain function, but initiates neuronal death and contributes to ischemic brain injury. Prolonged reductions in extracellular pH accompany ischemia and ASIC1a inhibition limits neurological damage. Yet, ASICs also play an important role in normal physiology and established models of ASIC-induced cell death make it difficult to develop strategies that specifically inhibit ASIC1a toxicity. Our preliminary data support a newer model of ASIC1a-induced cell death. Specifically, we have discovered that the toxic effect of ASIC1a can be eliminated by modification of the intracellular region of the channel or activation of the delta opioid receptor (DOR). An especially provocative aspect of these findings is that acidotoxicity is inhibited without a reduction in ASIC1a current, thereby suggesting that the toxic and physiological actions of the channel can be separated. Our central hypothesis is that DOR prevents acidotoxicity through signaling cascades, which act on the intracellular domain of ASIC1a to limit protein interactions required for toxicity. To test this hypothesis, we will define the mechanisms governing DOR action on ASIC1a and elucidate their role in ischemic injury in vivo. The outcomes of the proposed work will reveal novel regulatory mechanisms controlling ASIC1a-induced toxicity, suggest new interventions to mitigate ASIC-induced death using existing DOR agonists, and reveal strategies to separate the physiological and pathological actions of ASIC1a. These results will be significant as they are expected to have broad implications for the prevention of brain injury following ischemic stroke as well as other disorders where neuronal acidotoxicity plays a role.