Grant: CIHR Fellowship

Neurons communicate through electric signals that are initiated and propagated by microscopic gates called voltage-gated sodium (Nav) channels. Nav channels control the flow of charged particles into neurons to form electric pulses. Mutations in Nav channels cause defects in the opening and closing of the gates that result in neurological and muscle-related diseases such as epilepsy, paralysis, chronic pain, and cardiac arrhythmias. Interestingly, specific mutations in a particular Nav channel called Nav1.7 causes chronic pain, while other mutations can produce the opposite effect and result in insensitivity to pain. Nav channels are also affected by many neurotoxins that can keep the gates open or closed. How different mutations and neurotoxins result in different clinical outcomes remain unclear. Understanding the function of Nav channels have been hampered by a lack of information on the molecular structure of the gates. To unravel the mechanisms of Nav channels, we are using recent advances in electron cryomicroscopy technology to study the atomic structures of Nav1.7 with different neurotoxins. The results from the structural studies will then guide experiments to determine the function of specific parts of Nav channels by measuring the movement of charged particles passing through the gates using electrophysiology techniques. This research will uncover how different mutations and neurotoxins affect the structure and function of Nav channels and provide a foundation for understanding the mechanisms of electric conduction in neurons. Understanding the molecular basis of Nav channels in neuron communication would represent a fundamental step forward in neurobiology and may reveal new therapeutic strategies for treating neurological and cardiac diseases. In particular, Nav1.7 is the focus of this project and a target of interest for the treatment of pain. Hence, this research has significant health and commercial value.