Grant: Discovery Grants Program - Individual

At its most basic level our nervous system is an intricate circuit of specialized cells called neurons that communicate with each other using electrical signals. This process relies on proteins embedded in the neuronal membrane, called ion channels, whose activity both generates and propagates these electrical signals. Billions of years of evolution have led to a staggering array of ion channel diversity, with different ion channel types opening and closing in response to a variety of stimuli. Ligand-gated ion channels, which open upon binding small chemical ligands, are Nature's ultimate molecular sensors. They convert chemical signals into electrical impulses by coupling the binding of small molecules to the opening of a membrane-spanning ion conducting pore. In the short-term, our research aims to understand mechanisms of ligand-gated ion channel function. In the long-term, this insight will be used to predict how mutations and small molecules alter channel function, and guide the engineering of ligand-gated ion channels with desired activities. Currently, our ability to achieve these long-term objectives is limited by gaps in our understanding of channel structure, function, and mechanism. To uncover the structural and mechanistic basis of enigmatic ligand-gated ion channel functions, the proposed research will couple an innovative evolutionary biochemistry approach to single-molecule biophysical experiments. Evolutionary biochemistry involves charting the evolutionary history of proteins, with the goal of tracing the innovations in amino acid sequence that gave rise to modern day protein functions. The amino acid sequences of ancestral channels are first reconstructed, so that the ancestral channels can be `resurrected' and characterized at the single-molecule level. This emerging approach represents a rational way of exploring ligand-gated ion channel amino acid sequences to illuminate structure-function relationships that have stymied conventional approaches. The result will be a better understanding of fundamental aspects of ligand-gated ion channel structure, function, and mechanism. Ultimately, this will benefit Canadians and Canadian Pharma by [1] enabling the design of enhanced small molecule drugs that target ligand-gated ion channels, and [2] facilitating the engineering of channels with unique properties that will have broad diagnostic, therapeutic, and industrial applications. The proposed research will be carried out by a diverse team of postgraduate and undergraduate students, who will receive valuable training in technologies that are in high demand in the Canadian academic and industrial sectors. Through organizing and participating in Outreach activities, students will also receive training in the principles of equity, diversity, and inclusion, as well as in scientific communication. As a result, the proposed research will lead to fundamental new knowledge and expertise that will benefit Canadians for years to come.