Structural organization of anthelmintic target receptors

点击翻译按钮获取中文摘要

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.