Scientists Identify a Protein Channel that Mediates the
Body's Ability to Feel Frigid Temperatures
By Jason Socrates
A group of researchers from The Scripps Research Institute
(TSRI) and the Genomics Institute of the Novartis Research
Foundation (GNF) have identified and isolated a novel protein
that mediates the body's ability to sense cold through the
In an article that will appear in this week's issue of the
journal Cell, the group describes the "ion channel"
protein, called ANKTM1, which is the first noxious (painful)
cold receptor identified, and may be an important basic target
for pain-modulating drugs.
Despite the fact that researchers at several other laboratories
had previously identified receptors that sense hot temperatures,
warm temperatures, and cool temperatures, the protein that
detects cold temperatures had been conspicuously absent. "This
was one of the remaining puzzles," says TSRI Assistant Professor
of Cell Biology Ardem Patapoutian, who led the effort with
TSRI Research Associate Gina Story.
The cold receptor protein ANKTM1 was overlooked, note Patapoutian
and Story, because it is distantly related to the hot, warm,
and cool receptors. As such, ANKTM1 has very low sequence
homology, or DNA similarity, with these other proteins.
But when they studied it in the laboratory, Patatpoutian
and Story found that even though ANKTM1 did not "look" like
a temperature receptor, it sure acted like one. "We found
that if we applied very cold stimuli, the channel would open
in response," says Story.
Hot, Cold, and Everything In Between
Humans and other vertebrate animals use specialized sensory
neurons to detect temperature, pressure, and other physical
stimuli on the skin. These neurons are located in the spinal
column and are connected to the skin and organs through long
extensions known as axons.
On the surface of these axons are the protein channel molecules,
like ANKTM1 and its cousins the hot, warm, and cool receptors,
which span the axon's membrane, connecting the inside with
the outside. These receptors act like "molecular thermometers"
by opening and closing according to the temperature. At a
particular temperature, the receptors open. This allows an
influx of calcium ions into the axon, and this electrical
signal is relayed through the neuron to the brain.
The existence of specialized hot- and cold-neurons had been
known for years, but the molecules that actually sense the
temperatures and signal back to the neuron through the axon
were a complete mystery. That changed in 1997 when a group
cloned the first sensory molecule, a type of transient receptor
potential (TRP) channel called TRPV1. TRPV1 opens when it
senses hot temperaturesabove 42° C (108° F).
That discovery opened the floodgates for identifying temperature-detecting
proteins. Within a few years, several laboratories had identified
additional temperature-detecting proteins.
Last year, Patapoutian and his TSRI and GNF colleagues identified
and cloned a protein called TRPM8, which is the first-known
signaling molecule that helps the body sense cool temperatures.
The channel becomes activated below 25° C (77° F).
Similarly, the group also identified a type of TRP channel
called "TRPV3" that makes skin cells able to sense warm temperatures.
It is activated around 33° C (92° F).
How Low Can You Go?
In their current study, Patapoutian and Story demonstrate
that the channel ANKTM1 is inactive at room temperature and
higher, and only becomes active at "noxious" cold temperatures.
Below 15° C (59° F), the channel opens and allows
an influx of positively charged ions into the axon, an electrical
signal which is then communicated to the brain.
Biochemically, ANKTM1 is a bit of a puzzle because proteins
are normally more active at higher temperatures. Even more
bizarre is the fact that these cold-sensing ANKTM1 proteins
are coexpressed with their cousins, the hot-sensing TRPV1
proteins on the same neurons. This means that the same neuron
may be responsible for detecting hot and cold temperatures.
Scientists had long assumed that different neurons would
detect different stimuli and be responsible for communicating
those separately to the brain. But if the same neurons detect
hot and cold, how does the brain tell the two stimuli apart?
The answer, while unclear, may explain an old psychologist's
observation that humans cannot tell the difference between
a hot needlepoint and a cold needlepoint on their hand.
Significantly, ANKTM1's neuronal neighbor TRPV1 is involved
in inflammation and in communicating pain to the brain, and
several compounds that block TRPV1's action are currently
under investigation for chronic pain indications. Since ANKTM1
is expressed in the same neurons, it, too, may be a target
for pain therapeutics.
"This protein may be an important therapeutic target," says
Patapoutian, "because, like these other TRP channels, it may
be involved in inflammation and pain-mediation."
The research article "ANKTM1, a TRP-like Channel Expressed
in Nociceptive Neurons, Is Activated by Cold Temperatures"
is authored by Gina M. Story, Andrea M. Peier, Alison J. Reeve,
Samer R. Eid, Johannes Mosbacher, Todd R. Hricik, Taryn J.
Earley, Anne C. Hergarden, David A. Andersson, Sun Wook Hwang,
Peter McIntyre, Tim Jegla, Stuart Bevan, and Ardem Patapoutian
and appears in the March 21, 2003 issue of Cell.
The research was funded by the National Institutes of Health
and by a grant to TSRI from Novartis.
Some neurons like it hot (and cold)
The top panel shows
that cold-sensing ANKTM1 receptors (green fluorescent probes)
are expressed on cells distinct from those expressing the
cool-sensing TRPM8 receptors (red). However, in the bottom
panel, when ANKTM1 receptors (green) are visualized together
with the heat-sensitive TRPV1 receptor (red) , their overlap
(gold) shows that some neurons express both.