Voltage-gated sodium channels – Navs – are crucial for pain perception. This is illustrated by several human genetic syndromes leading to chronic pain or congenital painlessness. The type of Nav-mutation, its impact on neuron excitability as well as the affected channel subtype delineates a complex picture of the disorders. A detailed understanding of these pain disorders, however, was precluded because of the lack of direct structural information on human Nav channels.
With this project, we will address the new Nav gating concepts, investigate sodium channel dimerization and the effect of mutations on neuronal excitability, by using a multidisciplinary combination of electrophysiological investigations, induced patient-derived stem cells, atomistic molecular dynamics simulations, high-throughput genetics, machine learning, computer-controlled drug design and patient-associated sodium channel mutations addressed.
Our long-term goal is to integrate those comprehensive data to predict clinically relevant effects of sodium channel variants and their responsiveness to analgesic drugs. The results of this team effort are likely to yield in the long-term unifying predictive models that directly link pain-associated genetic Nav variants with changes in molecular biophysics, altered electrophysiological function, pharmacological responsiveness and clinical phenotypes.