A Nonproton Ligand Sensor in the Acid-Sensing Ion Channel

Ye Yu, Zhi Chen, Wei-Guang Li, Hui Cao, En-Guang Feng, Fang Yu, HongLiu, Hualiang Jiang, and Tian-Le Xu

Acid-sensing ion channels (ASICs) have long been
considered as extracellular proton (H+)-gated cation
channels, and peripheral ASIC3 channels seem to
be a natural sensor of acidic pain. Here, we report
the identification of a nonproton sensor on ASIC3.
We show first that 2-guanidine-4-methylquinazoline
(GMQ) causes persistent ASIC3 channel activation
at the normal pH. Using GMQ as a probe and combining
mutagenesis and covalent modification analysis,
we then uncovered a ligand sensor lined by
residues around E423 and E79 of the extracellular
''palm'' domain of the ASIC3 channel that is crucial
for activation by nonproton activators. Furthermore,
we show that GMQ activates sensory neurons and
causes pain-related behaviors in an ASIC3-dependent
manner, indicating the functional significance of
ASIC activation by nonproton ligands. Thus, natural
ligands beyond protons may activate ASICs under
physiological and pathological conditions through
the nonproton ligand sensor, serving for channel
activation independent of abrupt and marked
acidosis.