Heppenstall Group
Molecular physiology of somatosensation
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. For example, using a hemisected spinal cord preparation, we investigated the role of the neurotrophic factor BDNF in synaptic plasticity in the spinal cord. We demonstrated that BDNF is released from nociceptors onto spinal neurons and modulates spinal re ex activity. Furthermore, we were able to show that this occurs via an acute mechanism, supporting the idea that BDNF acts as a synaptic modulator. us, BDNF has a direct role in pain-related neurotransmission and might mediate the central sensitisation associated with chronic pain.
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 stomatin-like proteins and a family of ion channels called ASICs in this complex. Using cellular, electrophysiological and molecular imaging techniques we are probing the nature of interactions between these proteins and characterising their function in the mechanotransduction complex in detail.
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 Ca2+ directly activates TRPA1 via an EF-hand domain in the N-terminus of the protein and that Ca2+ is essential for normal activation of the channel by noxious chemicals. We are now interested in how TRP channels have evolved to become multimodal sensors across several phyla. Using a combination of computational and electrophysiological methods we are examining activation mechanisms in order to understand how these channels function as sensors for a diverse range of physical stimuli.
Future projects and goals
A major focus of the laboratory is to correlate cellular studies on somatosensation with observations made at the physiological level. To this end we are employing genetic approaches combined with electrophysiological and molecular imaging techniques. Future goals include:
- identifi cation 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.