Browsing by Subject "TRPV1"
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Item Open Access In Vitro Calcium Imaging of Magnetogenetic Ion Channels TRPV1FeRIC and TRPV4FeRIC(2018) Gibbs, EricFerritin-based magnetogenetic ion channels are promising new tools for non-invasive manipulation of ion channel activity. The use of these channels in animals has been promising but in vitro experiments in cultured cells have been inconclusive. This report focuses on channels TRPV1FeRIC and TRPV4FeRIC whose channel activity is reportedly sensitive to an alternating magnetic field (AMF) at 175 MHz. In vitro work on these channels has previously been done, but those experiments did not have the necessary controls and had significant confounding factors. This dissertation addresses these problems and redesigns AMF calcium imaging experiments to more accurately measure an AMF response. After many experiments and careful analysis, it is concluded that 175 MHz AMF exposure does not change intracellular calcium concentration in HEK 293T cells expressing TRPV1FeRIC or TRPV4FeRIC.
Item Open Access SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons.(Neuron, 2016-12-21) Han, Qingjian; Kim, Yong Ho; Wang, Xiaoming; Liu, Di; Zhang, Zhi-Jun; Bey, Alexandra L; Lay, Mark; Chang, Wonseok; Berta, Temugin; Zhang, Yan; Jiang, Yong-Hui; Ji, Ru-RongAbnormal pain sensitivity is commonly associated with autism spectrum disorders (ASDs) and affects the life quality of ASD individuals. SHANK3 deficiency was implicated in ASD and pain dysregulation. Here, we report functional expression of SHANK3 in mouse dorsal root ganglion (DRG) sensory neurons and spinal cord presynaptic terminals. Homozygous and heterozygous Shank3 complete knockout (Δe4-22) results in impaired heat hyperalgesia in inflammatory and neuropathic pain. Specific deletion of Shank3 in Nav1.8-expressing sensory neurons also impairs heat hyperalgesia in homozygous and heterozygous mice. SHANK3 interacts with transient receptor potential subtype V1 (TRPV1) via Proline-rich region and regulates TRPV1 surface expression. Furthermore, capsaicin-induced spontaneous pain, inward currents in DRG neurons, and synaptic currents in spinal cord neurons are all reduced after Shank3 haploinsufficiency. Finally, partial knockdown of SHANK3 expression in human DRG neurons abrogates TRPV1 function. Our findings reveal a peripheral mechanism of SHANK3, which may underlie pain deficits in SHANK3-related ASDs.Item Open Access Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain.(Proc Natl Acad Sci U S A, 2016-11-01) Sisignano, Marco; Angioni, Carlo; Park, Chul-Kyu; Meyer Dos Santos, Sascha; Jordan, Holger; Kuzikov, Maria; Liu, Di; Zinn, Sebastian; Hohman, Stephan W; Schreiber, Yannick; Zimmer, Béla; Schmidt, Mike; Lu, Ruirui; Suo, Jing; Zhang, Dong-Dong; Schäfer, Stephan MG; Hofmann, Martine; Yekkirala, Ajay S; de Bruin, Natasja; Parnham, Michael J; Woolf, Clifford J; Ji, Ru-Rong; Scholich, Klaus; Geisslinger, GerdChemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.Item Embargo The Mast Cell-Neuronal Axis in Anaphylaxis(2023) Bao, ChunjingIgE-mediated anaphylaxis is a dangerous systemic reaction to allergens and affect up to 50 million people in the United States, with the number of cases increasing every year. This reaction occurs when allergens enter the bloodstream and are recognized by IgE-sensitized mast cells (MCs), which leads to massive release of MC granules systemically. Mediators released from these granules have historically been believed to cause a sudden drop in blood pressure and core body temperature by promoting vasodilation and vascular leakage. However, here, we present evidence that in mice, the nervous system, specifically the thermoregulatory neural circuit, also plays a role in the drop in body temperature during IgE-mediated anaphylaxis. This neural circuit is activated by granule-borne chymase from mast cells and is sensed and encoded as a "pseudo-heat" signal, which leads to the activation of the warm thermoregulatory neural network. This activation then rapidly reduces thermogenesis in brown adipose tissue, contributing to hypothermia. Compared to wild-type mice, mice lacking chymase or TRPV1 (a receptor on sensory neurons) had a lesser drop in body temperature during IgE-mediated anaphylaxis. Additionally, systemic activation of TRPV1+ sensory neurons is sufficient to induce anaphylactic-like responses. Therefore, mast cell mediators, especially chymase, promote IgE-mediated anaphylaxis not only through their effects on blood vessels but also via the TRPV1-thermoregulatory neural circuit axis.
Item Open Access TMEM100, a regulator of TRPV1-TRPA1 interaction, contributes to temporomandibular disorder pain.(Frontiers in molecular neuroscience, 2023-01) Wang, Peng; Zhang, Qiaojuan; Dias, Fabiana C; Suttle, Abbie; Dong, Xinzhong; Chen, YongThere is an unmet need to identify new therapeutic targets for temporomandibular disorder (TMD) pain because current treatments are limited and unsatisfactory. TMEM100, a two-transmembrane protein, was recently identified as a regulator to weaken the TRPA1-TRPV1 physical association, resulting in disinhibition of TRPA1 activity in sensory neurons. Recent studies have also shown that Tmem100, Trpa1, and Trpv1 mRNAs were upregulated in trigeminal ganglion (TG) after inflammation of the temporomandibular joint (TMJ) associated tissues. These findings raise a critical question regarding whether TMEM100 in TG neurons is involved in TMD pain via regulating the TRPA1-TRPV1 functional interaction. Here, using two mouse models of TMD pain induced by TMJ inflammation or masseter muscle injury, we found that global knockout or systemic inhibition of TRPA1 and TRPV1 attenuated pain. In line with their increased genes, mice exhibited significant upregulation of TMEM100, TRPA1, and TRPV1 at the protein levels in TG neurons after TMD pain. Importantly, TMEM100 co-expressed with TRPA1 and TRPV1 in TG neurons-innervating the TMJ and masseter muscle and their co-expression was increased after TMD pain. Moreover, the enhanced activity of TRPA1 in TG neurons evoked by TMJ inflammation or masseter muscle injury was suppressed by inhibition of TMEM100. Selective deletion of Tmem100 in TG neurons or local administration of TMEM100 inhibitor into the TMJ or masseter muscle attenuated TMD pain. Together, these results suggest that TMEM100 in TG neurons contributes to TMD pain by regulating TRPA1 activity within the TRPA1-TRPV1 complex. TMEM100 therefore represents a potential novel target-of-interest for TMD pain.