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because they allow studying the coupling
of the energy collected from photons to
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Silencing Neurons with Light
Engineered channelrhodopsins conduct anions
rather than cations, changing the action
potential of neurons.
Neural networks control the activity of living individuals as central pro- cessing units control the functions
of modern computers. In a neuronal circuit,
information is transmitted through neurons
in the form of an action potential, which is
the electric potential difference between the
inside and the outside of a neuron. Ion channel proteins in the neuronal membrane act
as molecular devices that create and regulate
action potentials. A technology called optogenetics (1) allows neuronal circuits to be
manipulated by a combination of optics and
genetically targeted incorporation of microbial retinal binding proteins, called opsins
(2), into neurons. On pages 409 and 420 of
this issue, Wietek et al. and Berndt et al. (3,
4) use structure-based molecular engineering to invert the charge selectivity of different opsins, channelrhodopsins from algae,
resulting in much improved neuron silencers for use in optogenetics.
Through heterologous expression of
light-sensitive opsins, researchers can con-
trol the electric signals of neurons underly-
ing the activities of living animals with light.
Optogenetics thus provides precise neuronal
control that can resolve highly complex neu-
ronal activity in the brain, contributing, for
example, to understanding of psychiatric
disease states. However, microbial opsins
have limited functionality for optogenetics;
for example, their ion conductance and ion
selectivity are sufficient for microbial activ-
ity but are too low for the efficient control of
animal neuronal activity. The recent deter-
mination of the three-dimensional atomic
structure of a chimeric protein formed from
parts of two different channelrhodopsins
(5) from algae (6, 7) has opened the way
to rational molecular engineering of opsins
with novel functionalities.
Ion selectivity, a key functional component of ion channels, enables the regulation of action potentials (see the figure). In
the resting state of a neuron, the membrane
is polarized, with a membrane potential of
about –70 mV, through differences in ion
concentrations maintained by energy-driven
ion transporters. Upon light illumination,
channelrhodopsins conduct cations but not
anions (see the figure, panel A), thereby
depolarizing the membrane and inducing
Department of Chemistry, Graduate School of Science,
Kyoto University, Japan. E-mail: firstname.lastname@example.org-
K+ Na+ Cl–
A, Native channelrhodopsin
B, Wietek et al.’s engineered channel
C, Berndt et al.’s engineered channel
Better neuron silencers for optogenetics. Native channelrhodopsins conduct cations (A). In contrast, the
channelrhodopsins engineered by Wietek et al. (B) and by Berndt et al. (C) conduct chlorine anions. Different residues were mutated to create the two Cl– channels, with mutated residues shown in red (acidic), blue
(basic), and green (neutral). Mutated residues that do not change their polarity are omitted.