of the Max - MDC

Molecular Physiology of
Somatic Sensation
Gary R. Lewin
S
omatic sensation includes all those sensations that we consciously feel after stimulation of the
body, e.g. touch, warmth, cooling, or even limb movement. We experience these sensations as a
direct result of the activation of sensory neurons that are located in the dorsal root ganglia (DRG). In
our group we are interested in the molecular mechanisms that allow these neurons to transduce
these varied stimuli. Sensory neurons can, for example, detect changes in temperature of the skin in
non-noxious (not painful) as well as the noxious range (painful heat, or cold). They can also detect
gentle movement of the skin as well as intense mechanical stimulation of the skin that is normally
harmful. The nature of the transduction molecules involved together with the developmental events
that lead to specification of the appropriate sensory neuron sub-types are actively investigated the lab.
Molecular Basis of Mechanotransduction
Mechanotransduction is the process whereby receptor proteins
present in the endings of sensory neurons are able to
detect mechanical stimulation of the tissue they innervate.
We have used information from genetic experiments with
the nematode worm C.elegans to identify possible vertebrate
candidate proteins that might detect mechanical stimuli.
Genetic screens for touch insensitive worms have turned
up around 15 genes whose function is necessary to confer
touch sensitivity. These genes were named Mec for mechanically
insensitive and we have focused on identifying a role
mammalian orthologs of these genes in mammalian touch
sensation. Some of these genes encoded membrane ion
channels of the Deg/EnaC superfamily that were proposed
to open upon movement or displacement of the plasma
membrane. We have previously shown that some mammalian
Deg/EnaC channels belonging to the acid sensing
ion channel sub-family (ASIC channels) are required for
mice to properly discriminate touch stimuli. However, not
all ASIC member channels appear to be essential. The mec
genes in C.elegans have been proposed to work together in
a mechanotransduction complex. Another component of
this complex is the membrane protein MEC-2 that forms a
hairpin in the membrane and might regulate the activity of
the mechanotransducing channel. We have cloned new vertebrates
homologues of mec genes and have created mouse
mutant alleles to characterize the in vivo function of these
genes. MEC-2 is a member of a large family of proteins that
contain a stomatin-like (or PHB, prohibitin homology
domain). A member of this family called SLP3 (stomatin like
protein-3) was cloned by our group, and we subsequently
generated a mouse model with a null mutation of the SLP3
locus. In SLP3 mutant mice many mechanoreceptors (or
touch receptors) in the skin do not work in the absence of
the SLP3 protein. In order to analyze touch sensation in
mice we also developed a novel behavioral assay for touch
driven behavior in rodents. This assay is based on the ability
of mice to detect and react to gratings, which are fine
enough to have a textured quality. We were very pleased to
find that SLP3 mutant mice have severe deficits in their ability
to detect such textured surfaces.
Neuronal nanodetection
The mechanosensitive ion channels that are expressed by
sensory can be measured using high-resolution electrophysiology
techniques. We have recently shown that such ion
channels in the membranes of cultured DRG neurons can be
activated by stimuli in the nanometer range. Using a
nanomotor device very small stimuli (∼200 nm) are applied
to the neurite membrane of cultivated dorsal root ganglia.
The cells are simultaneously recorded using the whole cell
mode of the patch clamp amplifier and very rapidly activated
inward currents are observed with such stimuli. In many
cells the function of mechanosensitive ion channels
depends on the SLP3 gene. A major challenge in the next
few years is to define the nature of the ion channels that
depend on SLP3 function. Using such electrophysiological
techniques it became also clear that more than one type of
mechanosensitive channel is expressed in DRG neurons.
Hearing and touch
Hereditary deafness is a relatively common phenomenon
and a large number of genes have been identified that when
mutated lead to deafness in mouse and man. Recently we
have started working with several deaf mutant mice to
examine whether genes required for normal mechanotrans-
Function and Dysfunction of the Nervous System 173