alpha7 nicotinic acetylcholine receptor allosteric modulation and native structure

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Project Summary/Abstract: Nicotinic acetylcholine receptors are pentameric ligand-gated ion channels responsible for excitatory signaling throughout the nervous system. The α7 nicotinic receptor subtype is a widely expressed subtype that is unique among nicotinic receptors in that it forms a functional homopentamer, desensitizes rapidly, and is exceptionally permeable to Ca2+. It plays a prominent role in human disease with dysregulation of α7 linked to Alzheimer’s disease, schizophrenia, and inflammation. α7’s unique characteristics and involvement in disease have made it an attractive therapeutic target leading to the development of numerous compounds aimed at enhancing α7 activity. Among the most promising strategies are positive allosteric modulators (PAMs). PAMs increase receptor activity while maintaining the spatial and temporal characteristics of endogenous neurotransmission. Despite strong functional characterization, precise modulator binding sites and structural mechanisms of potentiation remain unknown, representing a major roadblock towards rational drug design. Moreover, while α7 can uniquely assemble as a functional homopentamer, it can also associate with other subtypes forming a heteromer, yielding increased diversity and altered channel properties. The degree of α7 channel diversity in native tissue is unclear. Thus, the major goal of this application is to resolve key questions related to the α7 subtype by elucidating receptor modulation mechanisms and determining the molecular structure of native α7. Building on previous work defining major gating cycle conformations, I aim to determine high resolution structures of α7 complexed with numerous allosteric modulators. In parallel, I will develop a method to purify native α7 from brain tissue and determine the structure of α7-containing channels using single particle cryo-EM. Taken together, this work will define mechanisms of receptor modulation and native α7 structure and subunit stoichiometry, enhancing our understanding of α7 biology and pharmacology. Furthermore, this work will provide a foundation for future native receptor purification and aid drug development towards the entire nicotinic receptor family.