Structural organization of anthelmintic target receptors

我的长期目标是用线虫作为所有动物的模型来理解肌肉活动的神经控制。神经和肌肉是动物特有的，它们决定了动物的生物学。它们受神经递质控制，这些神经递质与细胞表面受体结合，细胞在突触处相遇。当离子流过细胞膜时，这些受体将化学信号转化为电信号。它们起源于从单细胞祖先那里继承的受体，在数量和种类上扩大，识别不同的神经递质，激活和抑制反应。这是如何发生的尚不清楚，但允许复杂的，微调控制的感觉和运动。这些受体由五个亚基组成，这些亚基可以是相同的（同质），也可以是不同的（异质）。当它们的基因复制并承担新的功能时，新的受体继续出现。在这里，我将重点介绍它们是如何做到这一点的。我假设对于一个原始的同型受体，复制的基因是相同的并产生异型受体。基因进化为相互排斥，所以亚基占据了受体中相对于彼此的特定位置。在极端情况下，亚基产生单独的同质受体，根本不相互作用。亚基之间的物理接触以及细胞组装和加工受体的机制将参与其中。激活神经递质的任何变化都会发生在同质受体中，而只有一个基因需要改变。我的短期目标是：1)剖析两个同源受体亚基之间的相互作用，这两个受体亚基最近从一个同源祖先遗传下来，以确定是什么使它们分开。2)定义一个需要五个不同亚基的受体中亚基之间的物理位置和接触。Obj 3) Obj 2中的受体存在重复的亚基，只需要四个不同的亚基，而不是五个。我们将确定负责这种灵活性的机制以及如何确定亚基位置。目的4)我们发现了一类新的异聚受体，可以转换成不同的神经递质。我们将确定负责转换的氨基酸，以及它们是在同源祖先中出现的，还是在变成异源后出现的。目的5)我们从5种不同种类的寄生线虫中获得了一个同源受体，其体外功能从一种到另一种逐渐降低。这种受体存在于体内，所以在体外一定是缺少了什么。我们的目标是确定缺失的成分，并确定受体组装和加工的变化。这项工作将为理解神经递质信号的进化提供一个理论框架，从动物的起源到抗寄生虫药物靶受体的变化，一直持续到今天。在这样做的过程中，它将在可预见的将来为驱虫药靶标领域的研究提供动力，并提供一种方法来确定可能为加拿大生物技术工业提供新的药物靶标的新受体。

My Long Term Goals are to understand nervous control of muscular activity using nematodes as a model for all animals. Nerves and muscle are unique to animals and define their biology. They are controlled by neurotransmitters that bind to cell surface receptors where cells meet at a synapse. These receptors turn this chemical signal into an electrical one as ions flow across the membrane. They arose from a receptor inherited from single celled ancestors, expanding in number and variety, recognizing different neurotransmitters, activating and inhibiting responses. How this occurred is not known but allows complex, fine tuned control of the senses and movement. These receptors are made of five subunits that can be identical (homomeric) or different (heteromeric). New receptors continue to appear when their genes duplicate and take on new functions. Here I focus on how they do this. I hypothesize that for an original homomeric receptor, duplicate genes are identical and produce a heteromeric receptor. Genes evolve to exclude one another so subunits take up specific positions in the receptor relative to each other. In the extreme, subunits make separate homomeric receptors and do not interact at all. Physical contact between subunits as well as the cell machinery to assemble and process receptors will be involved. Any change in activating neurotransmitter will occur in homomeric receptors where only a single gene need change. My short term goals are Obj 1) Dissect the interactions between two homomeric receptor subunits, recently descended from a homomeric ancestor to identify what keeps them separate. Obj 2) Define the physical position and contact between subunits in a receptor that requires five different subunits. Obj 3) Duplicate subunits exist from the receptor in Obj 2 that only require four different subunits, not five. We will identify the mechanisms responsible for this flexibility and how subunit position is determined. Obj 4) We identified a new class of heteromeric receptor that switched to a different neurotransmitter. We will determine the amino acids responsible for the switch and if they arose in the homomeric ancestor, or after becoming heteromeric. Obj 5) We have a homomeric receptor from five different species of parasitic nematode whose function in vitro decreases progressively from one species to the next. The receptor exists in vivo so something must be missing in vitro. We aim to identify the missing component and determine the changes in receptor assembly and processing. This work will provide a theoretical framework to understand the evolution of neurotransmitter signalling in general, from the origin of animals to changes in anti-parasitic drug target receptors continuing today. In doing so it will provide an impetus for research in the field of anthelmintic drug targets for the foreseeable future and provide a means to identify new receptors that could present novel drug targets for the Canadian Biotechnology industry.