Research Interests: Summary: My group is interested in understanding how signals are received and transmitted by the nervous system. In one aspect of our research, we have exploited the power of natural products to elucidate molecular mechanisms of touch and pain sensation. For example, we have asked how capsaicin, the main pungent ingredient in "hot" chili peppers, elicits burning pain, and how menthol, the cooling agent in mint leaves, evokes an icy cool sensation. Using these agents as pharmacological probes, we have identified ion channels on sensory nerve fibers that are activated by heat or cold, providing molecular insight into the process of thermosensation. With the aid of genetic, electrophysiological, and behavioral methods, we are asking how these ion channels contribute to the detection of heat or cold, and how their activity is modulated in response to tumor growth, infection, or other forms of injury that produce inflammation and pain hypersensitivity. In addition to our work on somatosensation and pain, we also study the structure and function of specific neurotransmitter receptors, such as those activated by serotonin or extracellular nucleotides, and use genetic methods to identify roles for these receptors in physiological and behavioral processes, such as feeding, anxiety, pain, thrombosis, and cell growth and motility.
Publications
The structural basis of cold sensitivity.
A Cellular Basis for Heightened Gut Sensitivity in Females.
Population imaging of enterochromaffin cell activity reveals regulation by somatostatin.
Metabolic tuning facilitates nociceptor resilience to excitotoxicity.
Structural basis of TRPV1 modulation by endogenous bioactive lipids.
Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut.
Neuroendocrine cells initiate protective upper airway reflexes.
Structural basis of TRPV1 modulation by endogenous bioactive lipids.
Endogenous Opioid Signaling Regulates Proliferation of Spinal Cord Ependymal Cells.
A step-by-step protocol for capturing conformational snapshots of ligand gated ion channels by single-particle cryo-EM.
TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons.
Sensory TRP Channels in Three Dimensions.
Structural insights into TRPM8 inhibition and desensitization.
Membrane mimetic systems in CryoEM: keeping membrane proteins in their native environment.
Structural insight into TRPV5 channel function and modulation.
Tissue-specific contributions of Tmem79 to atopic dermatitis and mast cell-mediated histaminergic itch.
Structure of the human TRPM4 ion channel in a lipid nanodisc.
Pharmacology of the Nav1.1 domain IV voltage sensor reveals coupling between inactivation gating processes.
Lys49 myotoxin from the Brazilian lancehead pit viper elicits pain through regulated ATP release.
Editorial overview: molecular biology of sensation.
Stephen F. Heinemann: A true original.
Single particle electron cryo-microscopy of a mammalian ion channel.
TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids.
TRP channels and pain.
Receptor-targeting mechanisms of pain-causing toxins: How ow?
Signaling by sensory receptors.
Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli.
Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons.
Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells.
Radial stretch reveals distinct populations of mechanosensitive mammalian somatosensory neurons.
Multiple unbiased prospective screens identify TRP channels and their conserved gating elements.
Zebrafish TRPA1 channels are required for chemosensation but not for thermosensation or mechanosensory hair cell function.
Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels.
A yeast genetic screen reveals a critical role for the pore helix domain in TRP channel gating.
Fire in the hole: pore dilation of the capsaicin receptor TRPV1.
TRPA1 mediates formalin-induced pain.
4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1.
TRP channel activation by reversible covalent modification.
The P2Y12 receptor regulates microglial activation by extracellular nucleotides.
Neuroanatomical evidence for segregation of nerve fibers conveying light touch and pain sensation in Eimer's organ of the mole.
Toward better pain control.
International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels.
Pungent products from garlic activate the sensory ion channel TRPA1.
Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain.
A Nobel for smell.
Uropathic observations in mice expressing a constitutively active point mutation in the 5-HT3A receptor subunit.
Changes in anxiety-related behaviors and hypothalamic-pituitary-adrenal activity in mice lacking the 5-HT-3A receptor.
Co-localization of endomorphin-2 and substance P in primary afferent nociceptors and effects of injury: a light and electron microscopic study in the rat.
Immunoreactive TRPV-2 (VRL-1), a capsaicin receptor homolog, in the spinal cord of the rat.
International Union of Pharmacology. XLIII. Compendium of voltage-gated ion channels: transient receptor potential channels.
Lessons from peppers and peppermint: the molecular logic of thermosensation.
A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity.
Identification of a cold receptor reveals a general role for TRP channels in thermosensation.
The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors.
ATP transduces signals from ASGM1, a glycolipid that functions as a bacterial receptor.
The vanilloid receptor: a molecular gateway to the pain pathway.
Acid potentiation of the capsaicin receptor determined by a key extracellular site.
Capsaicin receptor in the pain pathway.
Impaired nociception and pain sensation in mice lacking the capsaicin receptor.
Sense and specificity: a molecular identity for nociceptors.
Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors.
Serotonin receptor knockouts: a moody subject.
Neuronal expression of the 5HT3 serotonin receptor gene requires nuclear factor 1 complexes.
Inactivation of a serotonin-gated ion channel by a polypeptide toxin from marine snails.
ATP receptors in sickness, pain and death.
Signaling by extracellular nucleotides.
Expression of a serotonin-gated ion channel in embryonic neural and nonneural tissues.
A new wave of serotonin receptors.
Expression cloning of an ATP receptor from mouse neuroblastoma cells.
Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha.
Nervous system distribution of the serotonin 5-HT3 receptor mRNA.
Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4).
Effects of 5-HT1C-receptor expression on cell proliferation control in hamster fibroblasts: serotonin fails to induce a transformed phenotype.
Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel.
Molecular biology of serotonin receptors.
The serotonin receptor subtype 2 locus HTR2 is on human chromosome 13 near genes for esterase D and retinoblastoma-1 and on mouse chromosome 14.
The 5HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors.
5-HT1c receptor is a prominent serotonin receptor subtype in the central nervous system.
Ectopic expression of the serotonin 1c receptor and the triggering of malignant transformation.
Molecular characterization of a functional cDNA encoding the serotonin 1c receptor.
Functional expression of the 5-HT1c receptor in neuronal and nonneuronal cells.
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