Harnessing acid-sensing ion channel toxins for therapeutic purposes

项目摘要/摘要 广泛性焦虑症和恐慌症是衰弱的疾病，导致严重的社会和 对患者的经济影响。抗抑郁药和苯二氮卓类药物是目前的前线 药物治疗，但两种药物都有不良副作用，嗯- 记录合规性问题和/或滥用可能性。酸敏离子通道(ASIC)代表 针对这些疾病的新的药物靶点和潜在的治疗途径。ASIC是一类pH- 激活的离子通道遍布神经系统，尤其是在 杏仁核。小鼠ASIC基因的遗传缺失导致几种缓解焦虑的表型，包括 在开阔场地迷宫实验中进行了更大的探索，减弱了音脚电击配对中的冻结和 杏仁核外侧突触间长时程增强的完全丧失。药理作用 用高选择性的Psalmooxin1肽抑制ASICs也能产生缓解焦虑的作用 当注射到啮齿动物体内时。不幸的是，psalmooxin1不容易通过血脑屏障。 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选择性毒素提供新的药物线索。要做到这一点，我们首先要结合 电生理学和高通量分析以定位人类ASIC1a和a之间的相互作用 选择性毒素。随后，我们将使用分子建模来预测hASIC1a-毒素结合位点。 最后，我们将使用电生理学和化学交联来测试这些建议的结合位点。 这些目标将共同确定高亲和力ASIC的结合部位和作用机制 选择性毒素，提供对经络的基础洞察，同时扩展治疗 兵工厂。考虑到ASIC参与了焦虑症，以及无数其他疾病， 这样的药理学进展可能会对医疗保健产生广泛的影响。

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.