Activation of Mechanosensitive Transient Receptor Potential/Piezo Channels in Odontoblasts Generates Action Potentials in Cocultured Isolectin B 4 –negative Medium-sized Trigeminal Ganglion Neurons

Eugenol, a natural capsaicin congener, is widely used in dentistry. Eugenol inhibits voltage-activated Na+ and Ca2+ channels in a transient receptor potential vanilloid 1 (TRPV1)-independent manner. We hypothesized that eugenol also inhibits voltage-gated K+ currents, and investigated this in rat trigeminal ganglion neurons and in a heterologous system using whole-cell patch clamping. Eugenol inhibited voltage-gated K+ currents, and the inhibitory effects of eugenol were observed in both capsaicin-sensitive and capsaicin-insensitive neurons. Pre-treatment with capsazepine, a well-known antagonist of TRPV1, failed to block the inhibitory effects of eugenol on K+ currents, suggesting no involvement of TRPV1. Eugenol inhibited human Kv1.5 currents stably expressed in Ltk− cells, where TRPV1 is not endogenously expressed. We conclude that eugenol inhibits voltage-gated K+ currents in a TRPV1-independent manner. The inhibition of voltage-gated K+ currents is likely to contribute to the irritable action of eugenol. Abbreviations: human Kv1.5 channel, hKv1.5; transient receptor potential vanilloid 1, TRPV1.

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Sex differences in mouse Transient Receptor Potential Cation Channel, Subfamily M, Member 8 expressing trigeminal ganglion neurons

PLoS ONE ◽

10.1371/journal.pone.0176753 ◽

2017 ◽

Vol 12 (5) ◽

pp. e0176753 ◽

Cited By ~ 3

Author(s):

Robert M. Caudle ◽

Stephanie L. Caudle ◽

Alan C. Jenkins ◽

Andrew H. Ahn ◽

John K. Neubert

Keyword(s):

Sex Differences ◽

Trigeminal Ganglion ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Cation Channel ◽

Trigeminal Ganglion Neurons ◽

Transient Receptor ◽

Ganglion Neurons

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Sumatriptan activates TRPA1

Cephalalgia Reports ◽

10.1177/2515816319847155 ◽

2019 ◽

Vol 2 ◽

pp. 251581631984715

Author(s):

Alexandru Babes ◽

Cristian Neacsu ◽

Michael JM Fischer ◽

Karl Messlinger

Keyword(s):

Side Effects ◽

Trigeminal Ganglion ◽

Transient Receptor Potential ◽

Animal Experiments ◽

Receptor Potential ◽

Membrane Currents ◽

Nociceptive Neurons ◽

Trigeminal Ganglion Neurons ◽

Transient Receptor ◽

Ganglion Neurons

Background: Migraine therapy with sumatriptan may cause adverse side effects like pain at the injection site, muscle pain, and transient aggravation of headaches. In animal experiments, sumatriptan excited or sensitized slowly conducting meningeal afferents. We hypothesized that sumatriptan may activate transduction channels of the “irritant receptor,” the transient receptor potential ankyrin type (TRPA1) expressed in nociceptive neurons. Methods: Calcium microfluorometry was performed in HEK293t cells transfected with human TRPA1 (hTRPA1) or a mutated channel (TRPA1-3C) and in dissociated trigeminal ganglion neurons. Membrane currents were recorded in the whole-cell patch clamp configuration. Results: Sumatriptan (10 and 400 µM) evoked calcium transients in hTRPA1-expressing HEK293t cells also activated by the TRPA1 agonist carvacrol (100 µM). In TRPA1-3C-expressing HEK293t cells, sumatriptan had hardly any effect. In rat trigeminal ganglion neurons, sumatriptan, carvacrol, and the transient receptor potential vanillod type 1 agonist capsaicin (1 µM) generated robust calcium signals. All sumatriptan-sensitive neurons (8% of the sample) were also activated by carvacrol (14%) and capsaicin (48%). In HEK293-hTRPA1 cells, sumatriptan (100 µM) evoked outwardly rectifying currents, which were almost completely inhibited by the TRPA1 antagonist HC-030031 (10 µM). Conclusion: Sumatriptan activates TRPA1 channels inducing calcium inflow and membrane currents. TRPA1-dependent activation of primary afferents may explain the painful side effects of sumatriptan.

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Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00002.2008 ◽

2008 ◽

Vol 294 (5) ◽

pp. G1288-G1298 ◽

Cited By ~ 92

Author(s):

Walter E. B. Sipe ◽

Stuart M. Brierley ◽

Christopher M. Martin ◽

Benjamin D. Phillis ◽

Francisco Bautista Cruz ◽

...

Keyword(s):

Sensory Neurons ◽

Action Potentials ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Mechanical Hyperalgesia ◽

Transient Receptor Potential Vanilloid ◽

Afferent Neurons ◽

Nociceptive Neurons ◽

Afferent Fibers ◽

Transient Receptor

Protease-activated receptor (PAR2) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR2 cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR2-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR2, and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4+/+ mice, intraluminal PAR2 activating peptide (PAR2-AP) exacerbated VMR to graded CRD from 6–24 h, indicative of mechanical hyperalgesia. PAR2-induced hyperalgesia was not observed in TRPV4−/− mice. PAR2-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4+/+ mice, but not from TRPV4−/− mice. The TRPV4 agonists 5′,6′-epoxyeicosatrienoic acid and 4α-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR2-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR2 increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR2-induced mechanical hyperalgesia and excitation of colonic afferent neurons.

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Pulsed infrared releases Ca2+ from the endoplasmic reticulum of cultured spiral ganglion neurons

Journal of Neurophysiology ◽

10.1152/jn.00740.2017 ◽

2018 ◽

Vol 120 (2) ◽

pp. 509-524 ◽

Cited By ~ 9

Author(s):

John N. Barrett ◽

Samantha Rincon ◽

Jayanti Singh ◽

Cristina Matthewman ◽

Julio Pasos ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Infrared Radiation ◽

Transient Receptor Potential ◽

Trp Channels ◽

Spiral Ganglion ◽

Receptor Potential ◽

Transient Temperature ◽

Spiral Ganglion Neurons ◽

Transient Receptor ◽

Ganglion Neurons

Inner ear spiral ganglion neurons were cultured from day 4 postnatal mice and loaded with a fluorescent Ca2+ indicator (fluo-4, -5F, or -5N). Pulses of infrared radiation (IR; 1,863 nm, 200 µs, 200–250 Hz for 2–5 s, delivered via an optical fiber) produced a rapid, transient temperature increase of 6–12°C (above a baseline of 24–30°C). These IR pulse trains evoked transient increases in both nuclear and cytosolic Ca2+ concentration ([Ca2+]) of 0.20–1.4 µM, with a simultaneous reduction of [Ca2+] in regions containing endoplasmic reticulum (ER). IR-induced increases in cytosolic [Ca2+] continued in medium containing no added Ca2+ (±Ca2+ buffers) and low [Na+], indicating that the [Ca2+] increase was mediated by release from intracellular stores. Consistent with this hypothesis, the IR-induced [Ca2+] response was prolonged and eventually blocked by inhibition of ER Ca2+-ATPase with cyclopiazonic acid, and was also inhibited by a high concentration of ryanodine and by inhibitors of inositol (1,4,5)-trisphosphate (IP3)-mediated Ca2+ release (xestospongin C and 2-aminoethoxydiphenyl borate). The thermal sensitivity of the response suggested involvement of warmth-sensitive transient receptor potential (TRP) channels. The IR-induced [Ca2+] increase was inhibited by TRPV4 inhibitors (HC-067047 and GSK-2193874), and immunostaining of spiral ganglion cultures demonstrated the presence of TRPV4 and TRPM2 that colocalized with ER marker GRP78. These results suggest that the temperature sensitivity of IR-induced [Ca2+] elevations is conferred by TRP channels on ER membranes, which facilitate Ca2+ efflux into the cytosol and thereby contribute to Ca2+-induced Ca2+-release via IP3 and ryanodine receptors. NEW & NOTEWORTHY Infrared radiation-induced photothermal effects release Ca2+ from the endoplasmic reticulum of primary spiral ganglion neurons. This Ca2+ release is mediated by activation of transient receptor potential (TRPV4) channels and involves amplification by Ca2+-induced Ca2+-release. The neurons immunostained for warmth-sensitive channels, TRPV4 and TRPM2, which colocalize with endoplasmic reticulum. Pulsed infrared radiation provides a novel experimental tool for releasing intracellular Ca2+, studying Ca2+ regulatory mechanisms, and influencing neuronal excitability.

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