Dr David Andersson
Ionic sensory transduction mechanisms
In animals, the family of TRP (transient receptor potential) ion channels fulfil important roles as transduction molecules, converting chemical and physical information into electrical signals. TRP channels are particularly prominent for transduction mechanisms in specialised sensory cells, where TRP channels are essential for the ability of animals to detect physical and chemical changes within the body, as well as in the external environment. In this way, animals exploit TRP channels to detect light, touch, temperature (hot and cold), pH and a wide range of chemicals. The functions of some of these ion channels are familiar to all of us. TRPV1 responds to stimulation with hot temperatures and the pungent ingredient capsaicin from chili peppers, which is why we perceive chilies as hot. Menthol from peppermint (and other chemicals that evoke a cooling sensation) shares a molecular target with cold temperatures in the ion channel TRPM8, whereas mustard, raw onion, tear gas and many other irritants evoke tearing, cough or pain by stimulating TRPA1. Experiments with transgenic mice have confirmed that without these ion channels, animals are unable to sense heat, cold and irritants, respectively. TRP channels in sensory neurons have attracted particular interest as potential drug targets for the development of novel analgesic drugs, since it has become clear that the expression of these ion channels determines which modalities different populations of sensory neurons respond to (e.g., heat, cold and irritants), since they act as the primary transducers of the painful stimuli.
Much is still unknown about the roles different members of this large family of ion channels fulfil in physiological and pathophysiological situations. This includes fundamental questions such as how many of these proteins are activated and regulated by endogenous molecules and how TRP channels in sensory neurons contribute to chronic pain conditions. This is the main focus of my lab. I use electrophysiological, microfluorometric, behavioural and molecular methods to elucidate sensory transduction mechanisms and to identify molecules or physical stimuli that act as agonists or modulators of sensory neuron TRP channels. Together with Prof. Stuart Bevan, these studies have previously led to the identification of the first endogenous agonists for TRPM8 and TRPA1 and identification of TRPA1 as the molecular target for paracetamol.
Figure 1. The left panel shows examples of voltage-clamp recordings from cells expressing TRPA1. Para-benzoquinone (p-BQ), a metabolite that is formed in vivo from paracetamol, evokes inward currents in a time and concentration-dependent manner. The right panel illustrates the effect of TRPA1 activation on action potential properties in a cultured dorsal root ganglion neuron in the current-clamp configuration. After stimulation of TRPA1 with p-BQ, there is a sustained reduction in the neuronal excitability (red trace) compared to before the p-BQ challenge (black trace). During the TRPA1 mediated depolarisation of the neuron it is not possible to evoke action potentials (blue trace).
Figure 2. Pseudocoloured images illustrating the intracellular Ca2+ concentration in dorsal root ganglion cultures from wildtype (Trpa1+/+) and TRPA1 knock-out (Trpa1+/+) mice before (background) and after application of the electrophilic paracetamol metabolite NAPQI (N-acetyl-p-benzoquinoneimine). NAPQI only stimulates a Ca2+-response in TRPA1 containing neurons.
- Andersson DA, Gentry C, Alenmyr L, Killander D, Lewis SE, Andersson A, Lewis, SE, Andersson A, Bucher B, Galzi JL, Sterner O, Bevan S. Hogestatt E D, Zygmunt PM. (2011). TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Delta(9)-tetrahydrocannabiorcol. Nat Commun 2: 551.
- Gentry C, Stoakley N, Andersson DA, Bevan S (2010). The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity. Mol Pain 6: 4.
- Rainey-Smith SR, Andersson DA, Williams RJ, Rattray M (2010). Tumour necrosis factor alpha induces rapid reduction in AMPA receptor-mediated calcium entry in motor neurones by increasing cell surface expression of the GluR2 subunit: relevance to neurodegeneration. J Neurochem 113(3): 692-703.
- Andersson DA, Gentry C, Moss S, Bevan S (2009). Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+. Proc Natl Acad Sci U S A 106(20): 8374-8379.
- Andersson DA, Gentry C, Moss S, Bevan S (2008). Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci 28(10): 2485-2494.
- Streng T, Axelsson HE, Hedlund P, Andersson DA, Jordt SE, Bevan S, et al. (2008). Distribution and function of the hydrogen sulfide-sensitive TRPA1 ion channel in rat urinary bladder. Eur Urol 53(2): 391-399.
- Andersson DA, Nash M, Bevan S (2007). Modulation of the cold-activated channel TRPM8 by lysophospholipids and polyunsaturated fatty acids. J Neurosci 27(12): 3347-3355.
- Andersson DA, Chase HW, Bevan S (2004). TRPM8 activation by menthol, icilin, and cold is differentially modulated by intracellular pH. J Neurosci 24(23): 5364-5369.