jm7b01072_si_002.csv (0.63 kB)
Molecular Basis for Allosteric Inhibition of Acid-Sensing Ion Channel 1a by Ibuprofen
dataset
posted on 2017-09-26, 12:37 authored by Timothy Lynagh, José Luis Romero-Rojo, Camilla Lund, Stephan A. PlessA growing body of evidence links
certain aspects of nonsteroidal
anti-inflammatory drug (NSAID) pharmacology with acid-sensing ion
channels (ASICs), a small family of excitatory neurotransmitter receptors
implicated in pain and neuroinflammation. The molecular basis of NSAID
inhibition of ASICs has remained unknown, hindering the exploration
of this line of therapy. Here, we characterized the mechanism of inhibition,
explored the molecular determinants of sensitivity, and sought to
establish informative structure–activity relationships, using
electrophysiology, site-directed mutagenesis, and voltage-clamp fluorometry.
Our results show that ibuprofen is an allosteric inhibitor of ASIC1a,
which binds to a crucial site in the agonist transduction pathway
and causes conformational changes that oppose channel activation.
Ibuprofen inhibits several ASIC subtypes, but certain ibuprofen derivatives
show some selectivity for ASIC1a over ASIC2a and vice versa. These
results thus define the NSAID/ASIC interaction and pave the way for
small-molecule drug design targeting pain and inflammation.