National Institute on Drug Abuse 5F31DA059092-04

alpha7 nicotinic acetylcholine receptor allosteric modulation and native structure

This award funds research to elucidate the modulation mechanisms and native structure of the α7 nicotinic acetylcholine receptor, a key receptor involved in neurological diseases, using cryo-electron microscopy to support drug development.

Description

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 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. The major goal of this project is to elucidate receptor modulation mechanisms and determine the molecular structure of native α7, including high-resolution structures of α7 complexed with allosteric modulators and native α7 channels using cryo-EM. This work aims to define mechanisms of receptor modulation and native α7 structure, enhancing understanding of α7 biology and pharmacology, and supporting drug development.

View original record