Harnessing acid-sensing ion channel toxins for therapeutic purposes

项目总结/摘要 广泛性焦虑症和恐慌症是导致严重的社交和心理障碍的衰弱性疾病。 对患者的经济影响。抗抑郁药和苯二氮卓类药物是目前的一线药物 药物治疗，但这两种药物类型都有不良的副作用，嗯- 记录的合规问题和/或滥用可能性。酸敏感离子通道（ASIC）代表 这是一个新的药物靶点和潜在的治疗途径。ASIC是一个家庭的pH- 在整个神经系统中发现的激活离子通道，特别是在 杏仁核小鼠中ASIC基因的遗传缺失导致几种抗焦虑表型，包括 在旷场迷宫实验中进行更大的探索，在音调-足电击配对中减弱冻结， 外侧杏仁核突触间长时程增强作用的完全丧失。药理 使用高选择性Psalmotoxin 1肽抑制ASIC也产生抗焦虑作用 注射到啮齿动物体内不幸的是，Psalmotoxin 1不易穿过血脑屏障 目前还没有高亲和力/高选择性的小分子ASIC药物。在此，我们建议 使用新描述的ASIC选择性毒素提供新药先导物。为此，我们将首先将联合收割机 电生理学和高通量测定，以绘制人ASIC 1a和 选择性毒素随后，我们将使用分子建模来预测hASIC 1a毒素结合位点。 最后，我们将使用电生理学和化学交联测试这些拟议的结合位点。 总之，这些目标将确定高亲和力ASIC的结合位点和作用机制 选择性毒素，提供对通道的基础性洞察，同时扩大治疗 医疗设备考虑到ASIC与焦虑症以及无数其他疾病的关系， 这种药理学的进步可能具有广泛的卫生保健意义。

PROJECT SUMMARY/ABSTRACT Generalized anxiety and panic disorder are debilitating disorders resulting in severe social and economic impact for patients. Antidepressants and benzodiazepines are the current frontline pharmacological treatments but both medication types come with undesirable side effects, well- documented compliance issues and/or abuse potential. Acid-sensing ion channels (ASICs) represent a new drug target and potential treatment avenue for these conditions. ASICs are a family of pH- activated ion channels found throughout the nervous system, being especially enriched in the amygdala. Genetic deletion of ASIC genes in mice results in several anxiolytic phenotypes including greater exploration in open field maze experiments, attenuated freezing in tone-foot shock pairing and the complete loss of long-term potentiation between synapses in the lateral amygdala. Pharmacological inhibition of ASICs using the highly selective psalmotoxin1 peptide also produces anxiolytic effects when injected into rodents. Unfortunately, psalmotoxin1 does not readily cross the blood-brain barrier and there are currently no high affinity/high selectivity small molecule ASIC drugs. Here we propose to furnish novel drugs leads using newly described ASIC selective toxins. To do this we will first combine electrophysiology and high throughput assays to map interactions between human ASIC1a and a selective toxin. Subsequently, we will use molecular modelling to predict hASIC1a-toxin binding sites. Finally, we will test these proposed binding sites using electrophysiology and chemical crosslinking. Together, these aims will identify the binding sites and mechanism of action of high affinity ASIC selective toxins, providing foundational insight into the channel while expanding the therapeutic armamentarium. Given the involvement of ASICs in anxiety disorders, and a myriad of other conditions, such pharmacological advances could have broad health care implications.