Neurons in Superficial Trigeminal Subnucleus Caudalis Responsive to Oral Cooling, Menthol, and Other Irritant Stimuli

The recent discoveries of cold-sensitive transient receptor potential (TRP) channels prompted us to investigate the responses of neurons in trigeminal subnucleus caudalis (Vc) to intraoral cooling and agonists of TRPM8 and TRPA1. Single units responsive to lingual cooling were recorded in superficial laminae of Vc in thiopental-anesthetized rats. All units responded to noxious heat and 88% responded to menthol. Responses increased with menthol concentration from 0.1 to 1% (6.4–64 mM) and plateaued at 10% (640 mM). Noxious cold-evoked responses were significantly enhanced after menthol in a concentration-dependent manner. Constant-flow application of 1% menthol elicited a phasic discharge that adapted over 2–8 min and significantly enhanced subsequent cold-evoked but not heat-evoked responses; vehicle (10% ethanol) was ineffective. Reapplication of menthol 15 min later elicited a significantly reduced response (self-desensitization). Vc units were similarly excited phasically by 1% menthol dissolved in 40% ethanol. The 40% ethanol briefly excited Vc units during the first minute and reduced subsequent responses to noxious heat and cold while exhibiting neither self-desensitization nor cross-desensitization to menthol. Menthol cross-desensitized Vc responses to 40% ethanol. Most menthol-responsive units also responded to the TRPA1 agonists cinnamaldehyde and mustard oil, and the TRPV1 agonist capsaicin. Units in superficial Vc receive convergent input from primary afferents that express TRPM8, TRPA1, and/or TRPV1 channels, either directly or indirectly via intersubnuclear pathways. The convergent nature of these units suggests a general role in signaling noxious stimuli.

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Mouse parabrachial neurons signal a relationship between bitter taste and nociceptive stimuli

10.1101/383661 ◽

2018 ◽

Author(s):

Jinrong Li ◽

Christian H. Lemon

Keyword(s):

Oral Delivery ◽

Transient Receptor Potential ◽

Bitter Taste ◽

Trp Channels ◽

Receptor Potential ◽

Protective Role ◽

Mustard Oil ◽

Noxious Heat ◽

Gustatory Neurons ◽

Pulse Stimulation

AbstractTaste and somatosensation both partly mediate protective behaviors. Bitter taste guides avoidance of ingestion of toxins while pain sensations, such as noxious heat, signal adverse conditions to ward off harm. Although brain pathways for taste and somatosensation are typically studied independently, prior data suggest they intersect, potentially reflecting their common protective role. To investigate this, we applied electrophysiologic and optogenetic techniques in anesthetized mice of both sexes to evaluate relationships between oral somatosensory and taste activity in the parabrachial nucleus (PbN), implicated for roles in gustation and pain. Spikes were recorded from taste-active PbN neurons tested with oral delivery of thermal and chemesthetic stimuli, including agonists of nocisensitive transient receptor potential (TRP) ion channels on somatosensory fibers. Gustatory neurons were also tested to follow electrical pulse stimulation of an oral somatosensory region of the spinal trigeminal subnucleus caudalis (Vc), which projects to the PbN. Neurons composed classic taste groups, including sodium, electrolyte, appetitive, or bitter oriented cells. Across groups, most neurons spiked to Vc pulse stimulation, implying trigeminal projections reach PbN gustatory neurons. Among such cells, agonists of nocisensitive TRP channels, including mustard oil, capsaicin, and noxious heat, were discovered to predominantly activate PbN bitter taste neurons tuned to the bitters quinine and cycloheximide. Such neurons populated the lateral PbN. Further, PbN bitter taste neurons showed suppressed oral nociceptive activity during optogenetic-assisted inhibition of the Vc, implying convergent trigeminal input contributed to such activity. Our results imply a novel role for PbN gustatory cells in crossmodal signaling related to protection.

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Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug auranofin

AJP Cell Physiology ◽

10.1152/ajpcell.00096.2012 ◽

2013 ◽

Vol 304 (4) ◽

pp. C354-C361 ◽

Cited By ~ 18

Author(s):

Noriyuki Hatano ◽

Hiroka Suzuki ◽

Yukiko Muraki ◽

Katsuhiko Muraki

Keyword(s):

Transient Receptor Potential ◽

Neuroblastoma Cell ◽

Receptor Potential ◽

Mustard Oil ◽

Cysteine Residues ◽

Induced Response ◽

Gold Compound ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Human Embryonic Kidney Cells

Gold compounds, which were widely used to treat rheumatoid arthritis, have been recently used as experimental agents for tumor treatment. Transient receptor potential (TRP) ankyrin repeat 1 (TRPA1) is a Ca2+-permeable ion channel that senses acute and inflammatory pain signals. Electrophilic compounds such as mustard oil and cinnamaldehyde activate TRPA1 by interacting with TRPA1 cysteine residues. Here we investigate the effects of the gold compound auranofin (AUR) on TRPA1 channels. Intracellular Ca2+ and whole cell patch-clamp recordings were performed on human embryonic kidney cells transiently expressed with TRPA1, TRP melastatin 8 (TRPM8), and vanilloid type TRP (TRPV1–4) channels. AUR stimulated TRPA1 in a concentration-dependent manner with a half-maximum potency of around 1.0 μM. The AUR-induced response was effectively blocked by HC030031, a TRPA1 antagonist. On the other hand, AUR failed to activate TRPM8 and TRPV1–4 channels, which are highly expressed in sensory neurons as nociceptors. The stimulatory effect on TRPA1 channels depended on the C414, C421, C621, and C633 cysteine residues and not on the inhibition of thioredoxin reductase by AUR. Moreover, AUR effectively activated TRPA1 channels expressed in human differentiated neuroblastoma cell lines. The study shows that AUR is a potent stimulator of TRPA1 channels.

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TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1715972115 ◽

2018 ◽

Vol 115 (7) ◽

pp. E1657-E1666 ◽

Cited By ~ 23

Author(s):

Miguel Ortíz-Rentería ◽

Rebeca Juárez-Contreras ◽

Ricardo González-Ramírez ◽

León D. Islas ◽

Félix Sierra-Ramírez ◽

...

Keyword(s):

Transient Receptor Potential ◽

Trp Channels ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Sigma 1 Receptor ◽

Trpv1 Channels ◽

Nociceptive Responses ◽

Sigma 1 ◽

Transient Receptor ◽

Thermal Stimuli

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.

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Role of TRP Channels in Shaping the Gut Microbiome

Pathogens ◽

10.3390/pathogens9090753 ◽

2020 ◽

Vol 9 (9) ◽

pp. 753 ◽

Cited By ~ 1

Author(s):

Ravinder Nagpal ◽

Santosh Kumar Mishra ◽

Gagan Deep ◽

Hariom Yadav

Keyword(s):

Gut Microbiome ◽

Transient Receptor Potential ◽

Fatty Acid Biosynthesis ◽

Trp Channels ◽

Receptor Potential ◽

Trp Channel ◽

Double Knockout ◽

Therapeutic Modalities ◽

Trpv1 Channels ◽

Noxious Chemicals

Transient receptor potential (TRP) channel family proteins are sensors for pain, which sense a variety of thermal and noxious chemicals. Sensory neurons innervating the gut abundantly express TRPA1 and TRPV1 channels and are in close proximity of gut microbes. Emerging evidence indicates a bi-directional gut–brain cross-talk in several entero-neuronal pathologies; however, the direct evidence of TRP channels interacting with gut microbial populations is lacking. Herein, we examine whether and how the knockout (KO) of TRPA1 and TRPV1 channels individually or combined TRPA1/V1 double-knockout (dKO) impacts the gut microbiome in mice. We detect distinct microbiome clusters among the three KO mouse models versus wild-type (WT) mice. All three TRP-KO models have reduced microbial diversity, harbor higher abundance of Bacteroidetes, and a reduced proportion of Firmicutes. Specifically distinct arrays in the KO models are determined mainly by S24-7, Bacteroidaceae, Clostridiales, Prevotellaceae, Helicobacteriaceae, Rikenellaceae, and Ruminococcaceae. A1KO mice have lower Prevotella, Desulfovibrio, Bacteroides, Helicobacter and higher Rikenellaceae and Tenericutes; V1KO mice demonstrate higher Ruminococcaceae, Lachnospiraceae, Ruminococcus, Desulfovibrio and Mucispirillum; and A1V1dKO mice exhibit higher Bacteroidetes, Bacteroides and S24-7 and lower Firmicutes, Ruminococcaceae, Oscillospira, Lactobacillus and Sutterella abundance. Furthermore, the abundance of taxa involved in biosynthesis of lipids and primary and secondary bile acids is higher while that of fatty acid biosynthesis-associated taxa is lower in all KO groups. To our knowledge, this is the first study demonstrating distinct gut microbiome signatures in TRPA1, V1 and dKO models and should facilitate prospective studies exploring novel diagnostic/ therapeutic modalities regarding the pathophysiology of TRP channel proteins.

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The nonselective cation channel TRPV4 inhibits angiotensin II receptors

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014325 ◽

2020 ◽

Vol 295 (29) ◽

pp. 9986-9997

Author(s):

Nicholas W. Zaccor ◽

Charlotte J. Sumner ◽

Solomon H. Snyder

Keyword(s):

Angiotensin Ii ◽

G Protein ◽

Transient Receptor Potential ◽

Trp Channels ◽

Receptor Potential ◽

Trp Channel ◽

Luciferase Assay ◽

Transient Receptor Potential Vanilloid ◽

Dependent Manner ◽

Transient Receptor

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.

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Structure of the human TRPM4 ion channel in a lipid nanodisc

Science ◽

10.1126/science.aar4510 ◽

2017 ◽

Vol 359 (6372) ◽

pp. 228-232 ◽

Cited By ~ 129

Author(s):

Henriette E. Autzen ◽

Alexander G. Myasnikov ◽

Melody G. Campbell ◽

Daniel Asarnow ◽

David Julius ◽

...

Keyword(s):

Conformational Changes ◽

Calcium Binding ◽

Transient Receptor Potential ◽

Trp Channels ◽

Receptor Potential ◽

Dependent Manner ◽

Calcium Binding Site ◽

Voltage Dependent ◽

Transient Receptor ◽

Lipid Nanodiscs

Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage-dependent manner but, unlike many other TRP channels, is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo–electron microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.

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Open Channel Block by Ca2+ Underlies the Voltage Dependence of Drosophila TRPL Channel

The Journal of General Physiology ◽

10.1085/jgp.200609659 ◽

2006 ◽

Vol 129 (1) ◽

pp. 17-28 ◽

Cited By ~ 22

Author(s):

Moshe Parnas ◽

Ben Katz ◽

Baruch Minke

Keyword(s):

Open Channel ◽

Transient Receptor Potential ◽

Voltage Dependence ◽

Trp Channels ◽

Divalent Cations ◽

Dependent Manner ◽

Channel Block ◽

Open Channel Block ◽

Gating Mechanism ◽

Voltage Dependent

The light-activated channels of Drosophila photoreceptors transient receptor potential (TRP) and TRP-like (TRPL) show voltage-dependent conductance during illumination. Recent studies implied that mammalian members of the TRP family, which belong to the TRPV and TRPM subfamilies, are intrinsically voltage-gated channels. However, it is unclear whether the Drosophila TRPs, which belong to the TRPC subfamily, share the same voltage-dependent gating mechanism. Exploring the voltage dependence of Drosophila TRPL expressed in S2 cells, we found that the voltage dependence of this channel is not an intrinsic property since it became linear upon removal of divalent cations. We further found that Ca2+ blocked TRPL in a voltage-dependent manner by an open channel block mechanism, which determines the frequency of channel openings and constitutes the sole parameter that underlies its voltage dependence. Whole cell recordings from a Drosophila mutant expressing only TRPL indicated that Ca2+ block also accounts for the voltage dependence of the native TRPL channels. The open channel block by Ca2+ that we characterized is a useful mechanism to improve the signal to noise ratio of the response to intense light when virtually all the large conductance TRPL channels are blocked and only the low conductance TRP channels with lower Ca2+ affinity are active.

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TRPV1 Inhibits the Ventilatory Response to Hypoxia in Adult Rats, but Not the CO2-Drive to Breathe

Pharmaceuticals ◽

10.3390/ph12010019 ◽

2019 ◽

Vol 12 (1) ◽

pp. 19 ◽

Cited By ~ 1

Author(s):

Luis Patrone ◽

Jaime Duarte ◽

Kênia Bícego ◽

Alexandre Steiner ◽

Andrej Romanovsky ◽

...

Keyword(s):

Transient Receptor Potential ◽

Trp Channels ◽

Ventilatory Response ◽

Pulmonary Ventilation ◽

Receptor Potential ◽

Current Data ◽

Adult Rats ◽

Cardiorespiratory Control ◽

Trpv1 Channels

Receptors of the transient receptor potential (TRP) channels superfamily are expressed in many tissues and have different physiological functions. However, there are few studies investigating the role of these channels in cardiorespiratory control in mammals. We assessed the role of central and peripheral TRPV1 receptors in the cardiorespiratory responses to hypoxia (10% O2) and hypercapnia (7% CO2) by measuring pulmonary ventilation ( V ˙ E ), heart rate (HR), mean arterial pressure (MAP) and body temperature (Tb) of male Wistar rats before and after intraperitoneal (AMG9810 [2.85 µg/kg, 1 mL/kg]) or intracebroventricular (AMG9810 [2.85 µg/kg, 1 µL] or AMG7905 [28.5 μg/kg, 1 µL]) injections of TRPV1 antagonists. Central or peripheral injection of TRPV1 antagonists did not change cardiorespiratory parameters or Tb during room air and hypercapnic conditions. However, the hypoxic ventilatory response was exaggerated by both central and peripheral injection of AMG9810. In addition, the peripheral antagonist blunted the drop in Tb induced by hypoxia. Therefore, the current data provide evidence that TRPV1 channels exert an inhibitory modulation on the hypoxic drive to breathe and stimulate the Tb reduction during hypoxia.

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Abstract 326: TRPV2 Regulates Cardiomyocyte Function via Altering Ca 2+ Cycling

Circulation Research ◽

10.1161/res.111.suppl_1.a326 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Xiaoqian Gao ◽

Sheryl Koch ◽

Min Jiang ◽

Nathan Robbins ◽

Wenfeng Cai ◽

...

Keyword(s):

Transient Receptor Potential ◽

Ventricular Myocytes ◽

Receptor Potential ◽

Ruthenium Red ◽

Transient Receptor Potential Vanilloid ◽

Dependent Manner ◽

Noxious Heat ◽

Cardiac Tissues ◽

Membrane Stretching ◽

Transient Receptor

TRPV2 is a member of transient receptor potential vanilloid (TRPV) family. As a Ca 2+ channel, it can detect various stimuli such as noxious heat (>52°C), membrane stretching, as well as a number of exogenous chemicals, including probenecid, 2-aminoethoxydiphenyl borate, and lysophospholipids. TRPV2 has been found in many tissue types, including neuron and kidney, but the function of TRPV2 in the heart is poorly understood. Here we show TRPV2 is involved in the Ca 2+ cycling process and then regulates the function of the cardiomyocyte. We identified the mRNA expression of TRPV2 in the cardiac tissues of mice using real-time PCR. By performing echocardiography we found that administration of probenecid, a selective TRPV2 agonist, increased cardiac ejection fraction in mice. This positive inotropic effect of probenecid was also shown in Langendorff perfused mice hearts as increased peak +dP/dt. In isolated ventricular myocytes, we found that probenecid significantly increased myocyte fractional shortening in a dose-dependent manner, which was fully blocked by ruthenium red, a non-selective TRPV2 blocker. We also performed fluorescent studies to examine myocyte Ca 2+ cycling. We found that probenecid significantly increased Ca 2+ transient and resting-state Ca 2+ sparks and this effect was eliminated by ruthenium red. When Ca 2+ storage in sarcoplasmic reticulum (SR) was depleted with caffeine, and SR Ca 2+ reuptake was blocked by thapsigargin at the same time, probenecid did not show any effects in either Ca 2+ transient or Ca 2+ sparks. Our patch clamp experiments indicate that probenecid treatment does not trigger any significant transmembrane Ca 2+ influx. These results point to the important role of TRPV2 in regulating SR Ca 2+ release. In conclusion, TRPV2 activation may contribute to increased SR Ca 2+ release, leading to the enhancement of myocyte contractility. Thus, TRPV2 plays a potentially important role in controlling the cellular function of heart.

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TRPM8 activation suppresses cellular viability in human melanoma

AJP Cell Physiology ◽

10.1152/ajpcell.00499.2007 ◽

2008 ◽

Vol 295 (2) ◽

pp. C296-C301 ◽

Cited By ~ 81

Author(s):

Hisao Yamamura ◽

Shinya Ugawa ◽

Takashi Ueda ◽

Akimichi Morita ◽

Shoichi Shimada

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Melanoma Cells ◽

Human Melanoma ◽

Specific Gene ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Trpm8 Channel ◽

Transient Receptor Potential Melastatin ◽

Inward Currents

The transient receptor potential melastatin subfamily (TRPM), which is a mammalian homologue of cell death-regulated genes in Caenorhabditis elegans and Drosophila, has potential roles in the process of the cell cycle and regulation of Ca2+ signaling. Among this subfamily, TRPM8 (also known as Trp-p8) is a Ca2+-permeable channel that was originally identified as a prostate-specific gene upregulated in tumors. Here we showed that the TRPM8 channel was expressed in human melanoma G-361 cells, and activation of the channel produced sustainable Ca2+ influx. The application of menthol, an agonist for TRPM8 channel, elevated cytosolic Ca2+ concentration in a concentration-dependent manner with an EC50 value of 286 μM in melanoma cells. Menthol-induced responses were significantly abolished by the removal of external Ca2+. Moreover, inward currents at a holding potential of −60 mV in melanoma cells were markedly potentiated by the addition of 300 μM menthol. The most striking finding was that the viability of melanoma cells was dose-dependently depressed in the presence of menthol. These results reveal that a functional TRPM8 protein is expressed in human melanoma cells to involve the mechanism underlying tumor progression via the Ca2+ handling pathway, providing us with a novel target of drug development for malignant melanoma.

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