DiagnosticsMapping The Dynamics Of Ion Channel Gating
Ion channels are integral proteins of most cell membranes and play
important roles in the nervous system, such as neurotransmitter secretion
and
muscle contraction, and several diseases are caused by mutations in ion
channels.
Understanding gating (which allows selective transport of ions) is
important for seeing how ion channels work and for developing effective
therapeutics. Nevertheless, fully outlining the gating mechanisms is
challenging, because ion channels normally undergo large conformational
changes
during gating and these changes cannot be directly detected by current
biophysical methods.
The recent collaboration between a computational biology group led by
Prof. Hualiang Jiang at the Shanghai Institute of Materia Medica, Chinese
Academy of Science (CAS), and a neuroscience group by Prof. Tian-le Xu at
the Institute of Neuroscience, CAS, whose results are published in this
week"s issue of the online open-access journal PLoS Biology provides a
good example of how to resolve this challenge.
These groups investigated the gating of the acid-sensing ion channel 1
(ASIC1), a key receptor for extracellular protons and a potential drug
target
for several disorders of central nervous system. Dr. Huaiyu Yang, a
postdoctoral fellow of Prof. Jiang simulated the dynamics behaviors of
ASIC1 at
the atomic level using computational methods, and found that a series of
collective motions among the domains and subdomains of ASIC1 correlated
with
its acid-sensing function. A rotation of the extracellular domain and the
combined motion of the "thumb and finger" domains induced by proton
binding drive a deformation from the extracellular domain to the
transmembrane domain, opening the channel pore by a "twist-to-open"
motion. At
the same time, Dr. Ye Yu, a postdoctoral fellow, and Weiguang Li, a
postgraduate student of Prof. Xu, carried out mutation and
electrophysiological
experiments to explore the deformation pathway proposed by computation,
and the results are compatible with the computational predictions. This
study
provides a clear picture of the correlation between the structural
dynamics of ASIC1 and its gating mechanism.
"The structure of ASIC1 provided an important basis for probing the
mechanism underlying the gating of ASICs," said Prof. Jiang, "and only
three
days after Jasti et al. published the X-ray crystal structure of chicken
ASIC1, we combined computational and experimental approaches to solve the
dynamics problem of ASIC1 gating. Our study is a fine example of studying
the complicated process of channel gating using computation and simulation
in combination with site-directed mutagenesis and electrophysiology."
Funding: This work was supported by the State Key Program of Basic
Research of China grants 2009CB918502 and 2006CB500803, China Postdoctoral
Science
Foundation grants 20080440095, and the National Natural Science Foundation
of China grants 20721003, 20720102040, 30830035, 30700145 and 30621062.
The
funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Competing interests statement: The authors declare that no competing
interests exist.
Citation:
"Inherent Dynamics of the Acid-Sensing Ion Channel 1 Correlates with the Gating Mechanism."
Yang H, Yu Y, Li W-G, Yu F, Cao H, et al. (2009)
PLoS Biol 7(7): e1000151. doi:10.1371/journal.pbio.1000151
PLoS Biology