Munich: A thoughtless brush with a hotplate and an encounter with the fiery
taste of a vindaloo curry are both painful experiences. These apparently
very different stimuli provoke the same burning sensation because they
both activate the same cell-surface receptor, TPRV1. TRPV1 is ultimately
responsible for the perception of the pain evoked both by high
temperatures and by the chemical irritants found in many spicy foods.
The receptor is mainly expressed by nerve fibers in sensory epithelia,
and it responds not only to high temperatures and compounds present in
chilis and other types of pepper, but also to electrical potentials,
spider toxins and acids. “One stimulus it does not respond to is light,”
says Dirk Trauner, Professor of Chemical Biology and Genetics at LMU. But recent work by his research team has now changed that.
TRPV-1 is a pore-shaped integral membrane protein and, when
activated, it allows positively charged ions to percolate into the cell.
This influx of cations alters the balance of charge across the
nerve-cell membrane. The resulting change in electrical potential is
propagated along the membrane, initiating a nerve impulse that is
transmitted to the brain, where it evokes the sensation of pain. “TRPV-1
is also activated by a variety of lipids, in particular by fatty acids
that are coupled to a particular structural element called a vanilloid
headgroup,” Trauner explains. “In this case, the efficacy of activation
depends both on the length of the fatty acid and its degree of
saturation, and is consequently very variable.” This versatility also
means that such fatty acids can provide ideal precursors for the
construction of light-sensitive switches that can activate TRPV-1 to
varying extents.
A box of tricks
Trauner’s team succeeded in inserting into the fatty-acid chain a
functional group whose structure can be altered by exposure to light of a
certain wavelength, allowing one to change the conformation of the
chain at will. “Using this strategy, we have designed a set of
light-sensitive fatty acids, which can serve as building blocks for
complex photo-activatable fat molecules,” says Trauner. “By modifying
these building blocks through the addition of a vanilloid head group, we
have synthesized a series of six compounds, which we call AzCAs. These
agents make it possible to accurately tune the level of activity of the
pain receptor.”
Thus, with the aid of the new molecules, pain-receptor function can
be regulated with unprecedented precision. They may therefore provide
new leads in the search for more effective therapies for the alleviation
of acute and chronic pain. They could, for instance, be used to enable
short-term opening of ion channels for local anesthetics, or to depress
the sensitivity of pain receptors by sporadic exposure to long-term
stimulation. In animal studies carried out in collaboration with Gary
Lewin’s group at the Max-Delbrück Centrum in Berlin, Trauner and his
colleagues have already shown that the propagation of pain signals can
indeed be controlled in whole tissues. “In addition to the precision
offered by this system, we were also impressed by the speed with which
the receptors reacted,” says Trauner. Capsaicin, the TRPV1 activator
found in chili peppers, stimulates the receptor rather slowly and
detaches from the receptor only when the ambient concentration of the
compound has fallen below a certain threshold. In contrast, AzCAs can be
administered in the deactivated state, activated with ultraviolet
light, and deactivated in a flash with a pulse of blue light. By this
means, the ability to perceive pain can be rapidly turned on and off.
The researchers now plan to test the effects of their
light-controlled switches in more complex neuronal model systems and in
vivo. “In addition, we are working on agents that respond to
illumination with red light, which would make cells located in deeper
tissue layers accessible to optical control,” says Trauner. “And in a
further project, we want to incorporate our diverse light-sensitive
fatty acids into more complex lipids, aiming to controlling other
proteins and cell functions with light. And, finally, we have paved the
way for photogastronomy.”
Nature Communications 2015