Investigations into ASIC1a-dependent neuronal death

酸敏感离子通道1a(Asic1a)是正常大脑功能所必需的，但也会引起神经元死亡。 并导致缺血性脑损伤。细胞外pH持续降低伴随着缺血和 ASIC1a抑制可限制神经损伤。然而，ASIC在正常的生理学和 已建立的ASIC诱导的细胞死亡模型使开发专门抑制 ASIC1a毒性。我们的初步数据支持ASIC1a诱导细胞死亡的新模型。具体来说，我们 已经发现ASIC1a的毒性效应可以通过修饰ASIC1a的胞内区来消除 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 研究结果是，在ASIC1a电流没有减少的情况下，酸毒性被抑制，从而表明 该通道的毒性和生理作用可以分离。我们的中心假设是DOR可以防止 通过信号级联作用于ASIC1a的胞内结构域以限制蛋白质的酸毒性 毒性所需的相互作用。为了检验这一假设，我们将定义管理DOR操作的机制 ASIC1a，并阐明其在体内缺血损伤中的作用。拟议工作的结果将揭示 控制ASIC1a诱导的毒性的新调节机制，建议新的干预措施来缓解 使用现有的DOR激动剂诱导ASIC死亡，并揭示了将生理性和 ASIC1a的病理行为。这些结果将是重要的，因为它们预计将具有广泛的 对预防缺血性中风后的脑损伤以及其他疾病的影响 神经元的酸中毒起着一定的作用。

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.