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Altitude, temperature, circadian rhythms and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Henning Wackerhage, Kenneth A. Dyar, Martin Schönfelder
A key requisite for thermoregulation is that some proteins must act as biological thermometers. In our body, the TRP (transient receptor potential) ion channels have that function. In contrast to a technical thermometer, however, there is not just one TRP ion channel but a family of TRP’s that are either warm-sensitive (TRPV1–4, TRP2–5) or cold-sensitive (TRPM8, TRPA1, TRPC5) and sense everything from cold pain, to cold, warmth and heat pain. Typically, once a certain temperature is reached, the TRP ion channels open and Na+ and Ca2+ ions flow into and depolarise any neuron that expresses these TRPs. Several knockout mouse models for the TRP ion channels have been generated and suggest that together, the TRPs sense temperature (42).
Nonclassical Ion Channels and Ischemia
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
TRP channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its expression is dramatically increased in numerous types of cancer [43]. In ischemia, myelin is damaged in Ca2+ involved pathway which is devoted to glutamate release activating NMDA receptors. The H+-gated [Ca2+]i elevation is mediated by channels with characteristics of TRPA1, which could be inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout, suggesting that TRPA1-containing ion channels performs a potential value in white matter ischemia [44]. In edema, ischemic stroke can be prevented by TRPV4, because TRPV4 is activated by body temperature and is enhanced by heating through glutamate receptors [45]. TRPV4 is a calcium-permeable cation channel that is also sensitive to cell swelling, modulating the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathways that regulate cell apoptosis when activated [46]. Up-regulation of TRPV4 is mediated through NR2B-NMDAR down-regulating the Akt signaling pathway for neurotoxicity [47]. In the penumbra, peri-infarct depolarizations (PIDs) are accompanied by strong intracellular calcium elevations in astrocytes and neurons, thereby negatively affecting infarct size and clinical outcome. TRPV4 channels contribute to calcium influx into astrocytes and neurons and subsequent extracellular glutamate accumulation ameliorate the PID-induced calcium overload during acute stroke [48]. TRPM2 has a high sensitivity to oxidative damage, so the oxidative stress and the release of extracellular Ca2+, hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate can change the activity of TRPM2 in the central nervous system and the immune system [49]. As a result, N-acetyl-l-cysteine (NAC) treatment can provide neuroprotection via regulation of TRPM2 [50]. Besides, the suppression of TRPM7 channels reduce delayed neuronal cell death and preserved neuronal functions in global cerebral ischemia [13]. And the TRPA1 is expressed by primary afferent nerve fibers, which is also a ‘receptor-operated’ channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch. It functions as a low-threshold sensor for structurally diverse electrophilic irritants, which may act as an attractive target for novel analgesic therapies [51]. Zn2+ is transferred from endolysosomal vesicles to the cytosol through the TRPML1 channel, and its sensitivity of Ca2+ play critical roles in neuronal function [52]. The TRPC5 ion channel is involved in ischemia which is related to endothelial cell sprouting and angiogenesis. Riluzole, the TRPC5 activator, are tested on ischemic injury regulating nuclear factor of activated T cell isoform c3 and angiopoietin-1 which could provide the mechanism for the angiogenic function of TRPC5 [53].
An overview of carbonic anhydrases and membrane channels of synoviocytes in inflamed joints
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
The TRPC1 and TRPC5 were expressed in secretory FLS76,77. The expression of oxidoreductase thioredoxin, a well-known oxidative stress marker, was increased in RA synovial fluids to counteract oxidative stress78–80. The thioredoxin was considered as a costimulatory component with cytokines in FLS81 and can be secreted82. Extracellular reduced form of thioredoxin enhanced the activities of TRPC1 and TRPC5 channels as new extracellular targets77. Inhibition of these channels by antibodies enhanced MMP secretion and suppressed the thioredoxin-mediated inhibitory effect on secretion77. More recently, the study of TRPC5 KO mice and inhibition of TRPC5 channels by antagonist addressed the enhanced inflamed joint and hyperalgesia76, suggesting that functional modulation of TRPC 1/5 could be considered as therapeutic targets for RA.
Odontoblasts are cold sensory cells in teeth
Published in Temperature, 2023
Pamela Sotelo-Hitschfeld, Laura Bernal, Katharina Zimmermann
In the mouse, the skin-saphenous nerve preparation served to decipher the molecular detection mechanisms of skin cold nociceptors and thermoreceptors [3]. Thus, in our study, we developed a new ex vivo model of the dental sensing system in the mouse [1]. This preparation allows to register propagated action potentials from the inferior alveolar nerve which innervates the mouse molars and incisor. In this novel preparation, we identified cold responses of almost 10-fold the size of skin cold nociceptors with most of them producing more than 100 action potentials in 1 min of cold exposure. These tooth cold nociceptors also produced several fold higher firing rates, although they were activated at lower temperatures than the skin nociceptors. Our pharmacological testing in this preparation included the effect of blockers on the three known cold sensitive TRP channels, TRPM8, TRPA1, and the transient receptor potential cation channel subfamily C member 5 (TRPC5). We found that the TRPC5 blocker HC070 and ML204 and the TRPA1 blocker HC03031 blocked the cold responses to a large degree while TRPM8 modulation, by agonist or blocker, was ineffective. In addition, we noted that the incidence of cold responses in jaw-nerve preparations of TRPC5 null mice was reduced by half. In line with the pharmacological experiments, tooth nociceptors in jaw preparations derived from TRPC5/TRPA1 double null mice had only few cold nociceptors and all had much reduced response magnitudes and firing rates. Thus, in contrast to the skin, where cold sensitivity is a synergism of TRPM8 and TRPA1, in teeth this function is a concert of TRPC5 and TRPA1.
Emerging therapeutic strategies for minimal change disease and focal and segmental glomerulosclerosis
Published in Expert Opinion on Investigational Drugs, 2018
Rossella Siligato, Valeria Cernaro, Chiara Nardi, Francesca De Gregorio, Guido Gembillo, Giuseppe Costantino, Giovanni Conti, Michele Buemi, Domenico Santoro
Another future target among slit diaphragm-associated proteins is transient receptor potential canonical 6 (TRPC6), whose gain-of-function mutations were identified in some forms of autosomal-dominant FSGS [132–135]. TRPC6, as well as TRPC5, is a cation channel activated by specific ligand-receptors bind, and allows intracellular Ca2+ flow. Angiotensin II, when binding angiotensin II type 1 receptor (AT1R), was demonstrated to enable TRPC6 action. Also suPAR was demonstrated to increase TRPC6 expression either directly, either inducing an increase of Nox2 production of cytosolic ROS, which in turn stimulate Src-tyrosine kinases to upregulate TRPC6. Also, mechanical stress on podocytes, such as hypo-osmotic stimuli, as well as also glomerular capillaries pulsations, can induce direct TRPC6 activation without G-protein involvement, leading to cytoskeleton dearrangement and the expression of calcineurin/Nuclear factor of activated T-cells (NFAT) pathway, which is associated with glomerulosclerosis and proteinuria. Finally, even microRNA-30 family demonstrated to intervene in the regulation of calcium/calcineurin signaling. In FSGS patients and mice models, miRNA-30 are typically downregulated, while TRPC6 and NFATC6 are highly expressed [136–138]. Other effects of TRPC6 regard the activation of Ca2+-dependent RhoA, which is thought to influence podocyte cytoskeletal stability and, in turn, enhances the expression of TRPC6 on plasma membrane of podocytes, with a positive feedback [139]. On these basis, ACEi, ARBs and calcineurin inhibitors could be a good choice in clinical practice to treat patients with TRPC6 mutations.