The fifth sense: temperature, touch, and pain detection
The sense of touch consists of the perception of discrete types of thermal, mechanical, and chemical stimuli. Electrophysiologists have long realized that recognition of touch is executed by neurons of restricted specificity, such that warm stimuli can activate a different class of neurons than cold stimuli do, for instance. However, little is known about the molecular basis of touch perception. Our lab is characterizing the genes involved in the first step of touch sensation: those that encode the molecular sensors of touch stimuli.
With the completion of the human genome project, we have powerful new methods to identify these elusive sensory molecules. We recently identified the first gene involved in our ability to sense cold temperatures. This gene, trpm8, encodes for a protein present at the plasma membrane of cold-sensing neurons that belongs to the Transient Receptor Potential (TRP) channel family. Interestingly, TRPM8 is also activated by menthol, a commonly-used cooling compound. More recently, we have identified a novel sensory channel that responds to warm and hot temperatures, TRPV3. TRPV3 is closely related to TRPM8 and represents the fourth TRP family member to sense temperature. We are continuing to identify additional sensory receptors, and we are also working towards understanding the mechanism of activation of these channels. How do these proteins actually sense temperature at the molecular level? As mentioned above, sensory neurons are highly specialized and are activated by distinct thermal and mechanical stimuli. How these neurons become specialized during development is not yet understood. In the adult, the sensory neuron subtypes are distinguished by many anatomical features but by few molecular markers. Perhaps the most extensive molecular understanding of developing somatic sensory neurons comes from studies of neurotrophins and their trk receptors. Our lab is building on these studies to extend our knowledge of the molecular processes that control the specification of these neuronal subtypes that arise from a shared precursor. We are using transgenic and genomic technologies to address these questions.
Our long-term goal is to synthesize an integrated picture of sensory neuron development and function. The two approaches discussed above will yield insights into the basic biology of the peripheral nervous system and may also have an impact on novel treatments for pain.
Macpherson LJ, Geierstanger BH, Viswanath V, Bandell M, Eid SR, Hwang S, Patapoutian A. The Pungency of Garlic: Activation of TRPA1 and TRPV1 in Response to Allicin. Curr Biol. 2005 May 24;15(10):929-34.
Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murray AN, Spencer KS, Andahazy M, Story GM, Patapoutian A. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science. 2005 Mar 4;307(5714):1468-72.
Rosenzweig M, Brennan KM, Tayler TD, Phelps PO, Patapoutian A, Garrity PA. The Drosophila ortholog of vertebrate TRPA1 regulates thermotaxis. Genes Dev. 2005 Feb 15;19(4):419-24. Epub 2005 Jan 28.
Moqrich A, et al. Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate. Nat Neurosci. 2004 Aug;7(8):812-8. Epub 2004 Jul 11.
Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004 Mar 25;41(6):849-57.
Patapoutian A, Peier AM, Story GM, Viswanath V. ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat Rev Neurosci. 2003 Jul;4(7):529-39.
Viswanath V, Story GM, Peier AM, Petrus MJ, Lee VM, Hwang SW, Patapoutian A, Jegla T. Opposite thermosensor in fruitfly and mouse. Nature. 2003 Jun 19;423(6942):822-3.
Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A. ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures. Cell. 2003 Mar 21;112(6):819-29.
Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P, Bevan S, Patapoutian A. A heat-sensitive TRP channel expressed in keratinocytes. Science. 2002 Jun 14;296(5575):2046-9.
Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T, Orth AP, Vega RG, Sapinoso LM, Moqrich A, Patapoutian A, Hampton GM, Schultz PG, Hogenesch JB. Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4465-70.
Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A trp channel that senses cold stimuli and menthol. Cell. 2002 Mar 8;108:705-15.