BBB seminar: Timothy Lynagh
Phylogenetics and an expanded genetic code uncover determinants of proton-sensing, ion conduction and NSAID sensitivity in acid-sensing ion channels
Sars International Centre for Marine Molecular Biology, University of Bergen
Acid-sensing ion channels (ASICs) are sodium channels activated by decreased extracellular pH. ASICs are expressed throughout the nervous system, contributing to nociception in the periphery and to pain, fear, and learning in the central nervous system. Relatively little was known about the molecular basis for ASIC function until recently, leading us to question their pharmacological modulation, their selective conduction of sodium ions and thus excitatory activity, and their sensitivity to protons.
Proton sensitivity had been described as a vertebrate-specific novelty within the protein family to which ASICs belong, but our investigation uncovered proton-gated ASICs throughout numerous invertebrates, enabling new hypotheses on the mechanism of activation by protons. By incorporating non-canonical amino acids into ASICs, we uncovered how the channel discriminates between sodium and potassium ions. Finally, our study of ASIC inhibition by the non-steroidal anti-inflammatory drug ibuprofen showed that the drug inhibits ASICs by engaging a crucial part of the channel and inducing opposing conformational changes to those induced by low pH.
Chairperson: Meg Veruki, Department of Biomedicine