RT Journal Article
SR Electronic
T1 β11-12 linker isomerization governs Acid-sensing ion channel desensitization and recovery
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 746271
DO 10.1101/746271
A1 Matthew Rook
A1 Abby Williamson
A1 John D. Lueck
A1 Maria Musgaard
A1 David M. MacLean
YR 2019
UL http://biorxiv.org/content/early/2019/08/24/746271.abstract
AB Acid-sensing ion channels (ASICs) are neuronal sodium-selective channels activated by reductions in extracellular pH. Structures of the three presumptive functional states, high-pH resting, low-pH desensitized, and toxin-stabilized open, have all been solved for chicken ASIC1. These structures, along with prior functional data, suggest that the isomerization or flipping of the β11-12 linker in the extracellular, ligand-binding domain is an integral component of the desensitization process. To test this, we combined fast perfusion electrophysiology, molecular dynamics simulations and state-dependent non-canonical amino acid cross-linking. We find that both desensitization and recovery can be accelerated by orders of magnitude by mutating resides in this linker or the surrounding region. Furthermore, desensitization can be suppressed by trapping the linker in the resting state, indicating that isomerization of the β11-12 linker is not merely a consequence of, but a necessity for the desensitization process in ASICs.