Molecular physiology of somatosensation
The Heppenstall group combines molecular, imaging and electrophysiological techniques to examine how sensory neurons turn information about touch and pain into electrical signals.
Previous and current research
Somatosensation is the process by which we sense touch and pain. It is dependent upon specialised sensory neurons which extend from the skin to the spinal cord and are tuned to detect mechanical, thermal and chemical stimuli. Surprisingly, the mechanisms that transduce these forces into electrical signals at the peripheral endings of sensory neurons are not well understood. Our research focuses on identifying and characterising these transduction components and exploring how they are altered during chronic pain states.
We use a combination of molecular, imaging and electrophysiological techniques to examine functional properties of sensory neurons at their peripheral and central terminals. At the molecular level, we are interested in mechanisms of touch sensitivity of sensory neurons. Normal mechanical sensitivity is dependent upon a complex of proteins that are localised at the peripheral endings of sensory neurons. Evidence supports a central role for the cytoskeleton in regulating the composition and function of this complex. Using cellular, electrophysiological and molecular imaging techniques we are characterising the contribution of the cytoskeleton, in particular microtubules to mechanotransduction.
Another focus of the group is to understand the biophysical properties of ion channels involved in sensory transduction. Much of our work has concentrated on the ion channel TRPA1, a member of the Transient Receptor Potential (TRP) family of channels. In mammals, TRPA1 is expressed by nociceptors and plays a key role in detecting noxious chemicals. We demonstrated that intracellular calcium ions directly activate TRPA1 via an EF-hand domain in the N-terminus of the protein and that calcium is essential for normal activation of the channel by noxious chemicals. We are now interested in how TRPA channels have evolved to sense diverse stimuli across different phyla – for example, in snakes and insects TRPA1 orthologues are activated by warm temperatures. Using a combination of molecular and electrophysiological techniques we have mapped the regions in Drosophila TRPA1 that are responsible for sensing temperature and described how single TRPA1 channels are activated by heat.
Future projects and goals
- Identification of novel genes involved in touch and pain.
- Mutagenesis of transduction channels and associated proteins to determine their mechanism of action.
- Tissue-specific and conditional mutagenesis of sensory-related genes in defined subpopulations of sensory neurons.
- Development of new techniques to measure functional properties of sensory neurons at their terminals.
The major focus of the laboratory is to correlate cellular studies on somatosensation with observations made at the physiological level. To this end we are developing genetic approaches that, combined with electrophysiological and molecular imaging techniques, will enable us to characterise sensory neurons in situ. A better understanding of sensory neuron function may ultimately lead to improved therapies for the treatment of chronic pain.