DOI: 10.1126/science.1244375
, 428 (2013);342Science
Gary R. Lewin
Natural Selection and Pain Meet at a Sodium Channel
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25 OCTOBER 2013 VOL 342 SCIENCE www.sciencemag.org428
PERSPECTIVES
I
n the animal kingdom, extreme conditions
drive adaptive change to enable
species to live in and exploit challenging
environments. Nociceptors—sensory fibers
activated by noxious stimuli to signal pain—
enable animals to detect and avoid potentially
harmful stimuli, presumably because such
stimuli lead to the experience of pain. Variation
in pain sensitivity has not traditionally
been considered as a trait that is selected for,
or against, in the race to adapt to new environments.
On page 441 of this issue, Rowe et al.
show that evolutionary change in a voltagegated
sodium channel (Nav) drives resistance
to painful neurotoxins that enables grasshopper
mice (Onychomys torridus) in the Arizona
desert to prey on an otherwise inaccessible
food source, namely bark scorpions
(Centruroides sculpturatus) (1).
Nociceptors detect a wide range of harmful
stimuli, such as mechanical insult, chemicals,
acid, or extreme temperature. Yet the
nociceptive systems that detect such hazards
are remarkably conserved throughout the animal
kingdom (2). Nociceptors relay damage
signals in the form of action potential trains
that travel long distances from skin to spinal
cord. Mammalian nociceptors are equipped
with a mix of voltage-gated sodium channels
that sustain action potential firing. Two critical
members of this mix are the tetrodotoxin
(TTX)–resistant Nav1.8 and TTX-sensitive
Nav1.7 channels (TTX is a pufferfish toxin
that potently blocks sodium channels). Both
channels are selectively expressed in nociceptors,
and gene knockout studies in mice
or their mutation in humans are associated
with reduced pain or sometimes a complete
absence of pain (3).
Rowe et al. began by observing that the
venom of the bark scorpion, native to theArizona
desert, causes intense behavior indicative
of pain in lab mice, probably by activating
the Nav1.7 channel. However, grasshopper
mice living in theArizona desert regularly
kill and consume bark scorpions, without any
apparent discomfort from multiple stings
experienced during prey capture. Recordings
from freshly isolated sensory neurons from
grasshopper mice and lab mice revealed that
the isolated bark scorpion venom strongly
activates lab mouse sensory neurons, but
strongly inhibited action potential firing in
grasshopper mouse sensory neurons.
The authors used pharmacological isolation
of the TTX-resistant Nav1.8 current
in isolated sensory neurons to show that the
Natural Selection and Pain Meet
at a Sodium Channel
EVOLUTION
Gary R. Lewin
Grasshopper mice can feed on toxic bark
scorpions because they have evolved resistance
to the pain normally caused by the toxin in
the scorpion sting.
Department of Neuroscience, Max Delbrück Center for
Molecular Medicine, Robert-Rössle str. 10, 13122 Berlin,
Germany. E-mail: glewin@mdc-berlin.de
lated into German for this reason. This may
be considered a variation of, or possibly an
addition to, the Weberian theory on the religious
origin of modern capitalism. The German
sociologist Max Weber argued that the
teaching of hard work and frugality, and
especially the view that economic success
in life was a sign of being chosen for a next
life, spurred entrepreneurship. Perhaps it was
not the religious teaching and moral values
of Protestantism that created an economic
growth impetus, but rather the latter’s emphasis
on the accumulation of human capital, of
men and women (4).
The Malthusian revolution plus the
increased participation of women in agriculture
and reduction in fertility—coupled,
in parts of Europe, with a new emphasis on
the accumulation of human capital and possibly
some religious fervor—would constitute
the perfect catalyst for the birth of capitalism
and the rapid social and economic growth
that followed. It was the complex interaction
of a plague, cultural values, accumulation of
human capital, and development of new technologies
that created the spark that ignited the
modern economic system.
References
1. N. Voigtländer, H.-J. Voth, Am. Econ. Rev. 103, 79
(2013).
2. A. Alesina et al., Q. J. Econ. 128, 469 (2013).
3. A. Alesina, P. Giuliano, N. Nunn, Am. Econ. Rev.Pap.
Proc. 101, 499 (2011).
4. S. O. Becker, L. Wessman, Q. J. Econ. 124, 531 (2009).
10.1126/science.1246228
Venom peptides
Activation
Activation
Nociceptor Nociceptor
Block
Grasshopper mouseMouse
Venom peptides
Bark scorpion
Pain No pain
TTX-resistant
Nav1.8 channel
TTX-resistant
Nav1.8 channel
TTX-sensitive
Nav1.7 channel
TTX-sensitive
Nav1.7 channel
Pain and gain. The bark scorpion toxin activates Nav1.7 channels in grasshopper mice and lab mice. But
in grasshopper mice, the toxin potently inhibits the Nav1.8 channel in the same sensory neurons, tipping
the balance to inhibit action potential firing in nociceptors. This evolutionary adaptation allows grasshopper
mice to feed on bark scorpions with impunity. In contrast, the lab mouse Nav1.8 channel is not blocked by
the toxin and the scorpion sting excites nociceptors, causing intense pain. CREDIT:P.HUEY/SCIENCE
Published by AAAS
www.sciencemag.org SCIENCE VOL 342 25 OCTOBER 2013 429
PERSPECTIVES
M
illions of patients undergo PET
(positron emission tomography)
imaging every year, but there is
a critical unmet need for new PET imaging
probes capable of diagnosing and monitoring
a multitude of diseases. One of the most
versatile radionuclides for PET imaging
is 18
F, but rapid chemical synthesis of any
probe based on 18
F is essential because its
physical half-life is only 110 min. Huiban
et al. (1) recently reported an improved
method for labeling trifluoromethylarenes
(Ar-CF3) with 18
F that could greatly facilitate
the development and adoption of new
PET probes and allow the site of action of
existing drugs to be identified.
The only PET probe that has achieved
widespread clinical application in the United
States thus far is 2-[18
F]fluoro-2-deoxy-Dglucose
([18
F]FDG; see the figure, panels A
and B), which images cancer metabolism by
pinpointing areas of high glucose usage (2,
3). Because cancer cells generally burn extra
glucose as fuel, FDG-PET provides clinicians
with a diagram of cancer cell activity
within the body.This method is now the standard
of care in oncology for diagnosis, staging,
and monitoring therapy. With the recent
development of scanners that combine PET
with computed tomography (CT), clinicians
can now compare three-dimensional anatomical
CT images with biochemical maps
of fuel consumption in cancer tissue. For the
past two decades, FDG has been the only 18
F
drug approved by the U.S. Food and Drug
Administration (FDA) for PET imaging.
Because PET-CT scans can reveal vital
information about the anatomical structure
within the body and its regional glucose consumption
during the same examination, this
method has the potential for understanding
many other pathophysiological processes. In
2012, the FDA approved a second PET drug,
Amyvid (florbetapir f18) (see the figure, panels
A and C) (4), for detecting β-amyloid
plaques, clumps of proteins that form around
neurons in the brain and contribute to the
development of Alzheimer’s disease (AD).
Amyvid is now being used for patient selecExpanding
the Scope of Fluorine
Tags for PET Imaging
CHEMISTRY
Lin Zhu,1,2,3
Karl Ploessl,2
Hank F. Kung2,4
A fast fluorination method can allow a wider
range of drug molecules to be imaged in the
body with positron emission tomography (PET).
scorpion toxin potently inhibited the TTXresistant
Nav1.8 channel current in grasshopper
mice neurons, but had no effect on this
current in lab mouse sensory neurons (see
the figure). They then cloned the Nav1.8 ion
channel of the grasshopper mouse to identify
the amino acids responsible for the channel
block produced by the scorpion venom. A
series of elegant domain switching and sitedirected
mutagenesis studies identified variations
in critical residues in domain II, a region
adjacent to the pore, that convert Nav1.8 into
a venom-sensitive channel. Just switching the
sequence order of an acidic glutamic acid (E)
and a hydrophilic glutamine (Q) separated by
two conserved residues was sufficient to render
grasshopper mouse Nav1.8 insensitive to
the venom, just like the lab mouse channel.
Animals in the order Rodentia make up
more than 40% of all mammalian species
and inhabit a vast number of often extreme
habitats worldwide. The role of acidic residues
in the grasshopper mouse Nav1.8 channel
is reminiscent of the way in which another
rodent species has coopted charged residues
in the Nav1.7 channel to increase inhibition
by acid. The subterranean naked mole
rat (Heterocephalus glaber), indigenous
to the dry high plateaus of east Africa, is in
no danger from scorpions, but is confronted
with high ambient CO2 in its crowded underground
habitat. High CO2 is painful, probably
because it is converted to acid in exposed
tissues. However, acid does not seem to
bother naked mole rats, because its Nav1.7 is
potently inhibited by acid to block nociceptor
firing. Evolution has driven changes in the
naked mole rat Nav1.7 channel sequence so
that two of three charged residues are altered
near the pore to potently increase channel
inhibition by protons (4).
It is striking that both the Nav1.7 and 1.8
channels, which are critical for the propagation
of pain information along nociceptor
axons to the central nervous system, have
undergone strong selective changes in different
animals. These changes probably promoted
by the extremity of the niches to which
the animals have adapted. Scorpion toxins
activate nociceptors and produce pain by dramatically
slowing the inactivation of sodium
channels like Nav1.7. It remains to be shown
whether the grasshopper mouse Nav1.7 chan-
nelisjustaspotentlyactivatedbycomponents
of bark scorpion venom as the same channel
is in lab mice. Other factors might contribute
to the grasshopper mouse’s insensitivity
to scorpion venom; for example, Rowe et al.
found that larger depolarizing impulses were
needed to evoke action potentials in sensory
neurons from grasshopper mice relative to
those from lab mice.
Pharmaceutical companies have a great
interest in developing new analgesic drugs
that do what the bark scorpion toxin does in
grasshopper mice: prevent pain. Evolution
has over millions of years achieved an analgesic
strategy tailored to one rodent species.The
challenge will be to identify channel sequence
variants that have allowed different species
to adapt to their unique environments. Gene
technology offers the possibility to reverse
engineer such variants into lab rodents. Drug
designers could well be able to take advantage
of the millions of years of natural selection to
find new approaches to tackle important drug
targets like sodium channels.
References and Notes
1. A. H. Rowe, Y. Xiao, M. P. Rowe, T. R. Cummins, H. H. Zakon,
Science 342, 441 (2013).
2. E. S. J. Smith, G. R. Lewin, J. Comp. Physiol. A 195, 1089
(2009).
3. A. Momin, J. N. Wood, Curr. Opin. Neurobiol. 18, 383
(2008).
4. E. S. J. Smith et al., Science 334, 1557 (2011).
Acknowledgments: I am grateful for many helpful comments
from members of the Lewin laboratory. The author’s
work was supported by grants from the European Research
Council and Deutsche Forschungsgemeinschaft.
1
Key Laboratory of Radiopharmaceuticals (Beijing Normal
University), Ministry of Education, Beijing 100875, People’s
Republic of China. 2
Department of Radiology, University of
Pennsylvania, Philadelphia, PA 19014, USA. 3
Beijing Institute
for Brain Disorders, Capital Medical University, Beijing,
People’s Republic of China. 4
Department of Pharmacology,
University of Pennsylvania, Philadelphia, PA 19014, USA.
E-mail: kunghf@mail.med.upenn.edu
10.1126/science.1244375
Published by AAAS