"Molecular Basis of Temperature Detection by Specialized Sensory Receptors"

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Date/Time:Monday, 28 Jan 2013 from 3:10 pm to 4:00 pm
Location:Hoover 1213
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Julio Cordero-Morales (Lilly Research Labs - University of California - San Francisco}

Primary afferent (somatosensory) neurons detect a range of physical and chemical stimuli, including temperature, pressure, and noxious irritants. The transient receptor potential (TRP) channel family has been shown to play a predominant role in these processes, particularly in regard to thermo- and chemosensitivity.

TRPA1, otherwise known as the ‘wasabi receptor’, is expressed by primary afferent sensory neurons of the pain pathway, where it functions as a sensor of environmental and endogenous chemical irritants, and contributes to cellular mechanisms underlying inflammatory pain. In my research using an unbiased transcriptional profiling approach I identified TRPA1 channels as infrared receptors in snakes sensory nerve fibers. Thus, snakes detect infrared signals through a mechanism involving radiant heat rather than a photochemical process. These results illustrate the broad evolutionary tuning of transient receptor potential (TRP) channels as thermosensors in the vertebrate nervous system. By comparing human and rattlesnake TRPA1 channels, I have identified two portable heat sensitive modules within the ankyrin repeat-rich amino-terminal cytoplasmic domain of the snake orthologue. Chimeric channel studies further demonstrate that sensitivity to chemical stimuli and modulation by intracellular calcium also localize to the N-terminal ankyrin repeat-rich domain, identifying this region as an integrator of diverse physiological signals that regulate sensory neuron excitability. These findings represent the first functional demonstration that temperature sensitivity can be faithfully and precisely transferred from a heat-sensitive to an -insensitive ortholog ion channel while also identifying portable modules that specify thermosensitivity.

Mammalian TRPV1 is a sensory receptor activated by noxious heat (>42 °C), capsaicin (the pungent ingredient of “hot†chili peppers), toxins, and proalgesic inflammatory agents (e.g., extracellular protons and bioactive lipids) that are produced in response to tissue injury. Vampire bats also have the ability to detect infrared radiation as a means of locating hotspots on warm-blooded prey. My research shows that vampire bats use RNA splicing in the TRPV1 gene to generate a channel with a truncated C-terminus that displays a reduced thermal activation threshold (>30 °C). Therefore, vampire bats expand the proteome by using a hypersensitive TRPV1 splice variant to detect infrared radiation. These findings reveal a novel molecular mechanism for physiological tuning of thermosensory nerve fibers.

I am interested in studying the physiology and biophysics of membranes proteins, specifically ion channels. My previous research in the laboratory of Dr. Eduardo Perozo, a world-class leader in the study of structure-function of ion channels, involved the study of the mechanism of inactivation in prokaryotic (KcsA) and eukaryotic (Shaker, Kv1.2, hERG, and BK) K+ channels. My graduate research projects gave me expertise in molecular biology, biochemistry, X-ray crystallography, and EPR spectroscopy. During my graduate studies I have published articles in prominent peer-reviewed journals and received the Outstanding Graduate Student award in 2007 from the University of Virginia together with the Student Research Achievement award in 2008 from the Biophysical Society.

For my postdoctoral research I joined the laboratory of Dr. David Julius, a pioneer in the discovery and characterization of ion channels in the somatosensory system. During this period, I was awarded with a prestigious postdoctoral fellowship from the Life Sciences Research Foundation (sponsored by Lilly Research Laboratories). I extended my training to include sensory neuron culture, calcium imaging, and electrophysiology (neurons, HEK293 and CHO cells, and Xenopus oocytes). In addition, I developed tools to purify eukaryotic membrane proteins from both insect and mammalian cells for biochemical and structural studies. Combining these techniques, I asked whether discrete structural motifs modulate or specify the response to physical and chemical stimuli in TRPV1 and TRPA1 (capsaicin and wasabi receptors, respectively). My postdoctoral research has contributed to four publications in prominent peer-reviewed journals.

My future goal is to lead an academic research laboratory to understand the relationship between structure and function of ion channels involved in somatosensation. Chronic pain is a debilitating condition that decreases the quality of life of affected individuals; the detection of painful stimuli involves ion channels at the peripheral terminals of specialized sensory neurons called nociceptors. These ion channels are remarkable because they respond to a broad range of physical (e.g., heat, cold, and pressure) and chemical (e.g., acid, irritants, and inflammatory mediators) stimuli that depolarize sensory neurons to elicit or intensify inflammatory pain. My research will focus on the study of the molecular principles underpinning the structure and function of sensory receptors by investigating how different stimuli induce structural rearrangements upon gating and by identifying regions involved in conferring sensitivity to local anesthetics. To address these questions it is required to combine multidisciplinary approaches like molecular biology and biochemical procedures, together with electrophysiological, X-ray crystallographic, and spectroscopic methods. My future research will continue to make important in-roads into the areas of structural biology, sensory physiology, nociception, and mechanisms of drug interaction.