Journal articles on the topic 'Transient receptor potential receptors'
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Shioya, Takanobu, Kazuhiro Sato, Masaaki Sano, and Hiroyuki Watanabe. "Transient receptor potential (TRP) channel and cough." Folia Pharmacologica Japonica 131, no. 6 (2008): 417–22. http://dx.doi.org/10.1254/fpj.131.417.
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Zhang, Hongyu, Peter J. Wickley, Sayantani Sinha, Ian N. Bratz, and Derek S. Damron. "Propofol Restores Transient Receptor Potential Vanilloid Receptor Subtype-1 Sensitivity via Activation of Transient Receptor Potential Ankyrin Receptor Subtype-1 in Sensory Neurons." Anesthesiology 114, no. 5 (May 1, 2011): 1169–79. http://dx.doi.org/10.1097/aln.0b013e31820dee67.
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Background Cross talk between peripheral nociceptors belonging to the transient receptor potential vanilloid receptor subtype-1 (TRPV1) and ankyrin subtype-1 (TRPA1) family has been demonstrated recently. Moreover, the intravenous anesthetic propofol has directly activates TRPA1 receptors and indirectly restores sensitivity of TRPV1 receptors in dorsal root ganglion (DRG) sensory neurons. Our objective was to determine the extent to which TRPA1 activation is involved in mediating the propofol-induced restoration of TRPV1 sensitivity. Methods Mouse DRG neurons were isolated by enzymatic dissociation and grown for 24 h. F-11 cells were transfected with complementary DNA for both TRPV1 and TRPA1 or TRPV1 only. The intracellular Ca concentration was measured in individual cells via fluorescence microscopy. After TRPV1 desensitization with capsaicin (100 nM), cells were treated with propofol (1, 5, and 10 μM) alone or with propofol in the presence of the TRPA1 antagonist, HC-030031 (0.5 μM), or the TRPA1 agonist, allyl isothiocyanate (AITC; 100 μM); capsaicin was then reapplied. Results In DRG neurons that contain both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in DRG neurons containing only TRPV1 receptors, exposure to propofol or AITC after desensitization did not restore capsaicin-induced TRPV1 sensitivity. Similarly, in F-11 cells transfected with both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in F-11 cells transfected with TRPV1 only, neither propofol nor AITC was capable of restoring TRPV1 sensitivity. Conclusions These data demonstrate that propofol restores TRPV1 sensitivity in primary DRG neurons and in cultured F-11 cells transfected with both the TRPV1 and TRPA1 receptors via a TRPA1-dependent process. Propofol's effects on sensory neurons may be clinically important and may contribute to peripheral sensitization to nociceptive stimuli in traumatized tissue.
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White, John P. M., Mario Cibelli, Antonio Rei Fidalgo, Cleoper C. Paule, Faruq Noormohamed, Laszlo Urban, Mervyn Maze, and Istvan Nagy. "Role of Transient Receptor Potential and Acid-sensing Ion Channels in Peripheral Inflammatory Pain." Anesthesiology 112, no. 3 (March 1, 2010): 729–41. http://dx.doi.org/10.1097/aln.0b013e3181ca3179.
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Pain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the context of surgery, its aftermath, or in the practice of pain medicine. Inflammatory agents, released as components of the body's response to peripheral tissue damage or disease, are now known to be collectively capable of activating transient receptor potential vanilloid type 1, transient receptor potential vanilloid type 4, transient receptor potential ankyrin type 1, and acid-sensing ion channels, whereas individual agents may activate only certain of these ion channels. These ionotropic receptors serve many physiologic functions-as, indeed, do many of the inflammagens released in the inflammatory process. Here, we introduce the reader to the role of these ionotropic receptors in mediating peripheral pain in response to inflammation.
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Andrzejewska, Angelika, Klaudia Staszak, Marta Kaczmarek-Ryś, Ryszard Słomski, and Szymon Hryhorowicz. "Understanding cannabinoid receptors: structure and function." Folia Biologica et Oecologica 14 (December 30, 2018): 1–13. http://dx.doi.org/10.1515/fobio-2017-0004.
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The endocannabinoid system (ECS) consists of the endocannabinoids, cannabinoid receptors and the enzymes that synthesize and degrade endocannabinoids. The whole EC system plays an important role in the proper functioning of the central and autonomic nervous system. ECS is involved in the regulation of the body energy and in the functioning of the endocrine system. It can affect on the regulation of emotional states, motoric movement, operations of the endocrine, immune and digestive system. Many of the effects of cannabinoids are mediated by G coupled –protein receptors: CB1, CB2 and GPR55 but also of transient receptor potential channels (TRPs) which not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides. In this review work we briefly summarize the role and action of cannabinoid receptors CB1 and CB2, protein-coupled receptor 55 (GPR55) and transient receptor potential vanilloid 1 (TRPV1).
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Toschi, Andrea, Giorgia Galiazzo, Andrea Piva, Claudio Tagliavia, Gemma Mazzuoli-Weber, Roberto Chiocchetti, and Ester Grilli. "Cannabinoid and Cannabinoid-Related Receptors in the Myenteric Plexus of the Porcine Ileum." Animals 11, no. 2 (January 21, 2021): 263. http://dx.doi.org/10.3390/ani11020263.
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An important piece of evidence has shown that molecules acting on cannabinoid receptors influence gastrointestinal motility and induce beneficial effects on gastrointestinal inflammation and visceral pain. The aim of this investigation was to immunohistochemically localize the distribution of canonical cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) and the cannabinoid-related receptors transient potential vanilloid receptor 1 (TRPV1), transient potential ankyrin receptor 1 (TRPA1), and serotonin receptor 5-HT1a (5-HT1aR) in the myenteric plexus (MP) of pig ileum. CB1R, TRPV1, TRPA1, and 5-HT1aR were expressed, with different intensities in the cytoplasm of MP neurons. For each receptor, the proportions of the immunoreactive neurons were evaluated using the anti-HuC/HuD antibody. These receptors were also localized on nerve fibers (CB1R, TRPA1), smooth muscle cells of tunica muscularis (CB1R, 5-HT1aR), and endothelial cells of blood vessels (TRPV1, TRPA1, 5-HT1aR). The nerve varicosities were also found to be immunoreactive for both TRPV1 and 5-HT1aR. No immunoreactivity was documented for CB2R. Cannabinoid and cannabinoid-related receptors herein investigated showed a wide distribution in the enteric neurons and nerve fibers of the pig MP. These results could provide an anatomical basis for additional research, supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders in porcine enteropathies.
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Manolache, Alexandra, Teodora Stratulat, and Alexandru Babeș. "Modulation of Transient Receptor Potential (TRP) channels by tyrosine phosphorylation." Reviews in Biological and Biomedical Sciences 3, no. 1 (July 4, 2020): 77–87. http://dx.doi.org/10.31178/rbbs.2020.3.1.5.
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Transient Receptor Potential (TRP) channels are a superfamily of polymodal, non-selective receptors, expressed in the nervous system and several other tissues, where they play many physiological or pathological roles. TRP channels are sensitive to a diverse range of stimuli, such as temperature, osmolarity, oxidative stress, external compounds and intracellular signaling molecules. The activity of TRP channels can be modulated by protein phosphorylation, including tyrosine phosphorylation. In this review, we present the studies carried out so far regarding the modulation of TRP channels by tyrosine phosphorylation.
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Ditting, Tilmann, Roland Veelken, and Karl F. Hilgers. "Transient Receptor Potential Vanilloid Type 1 Receptors in Hypertensive Renal Damage." Hypertension 52, no. 2 (August 2008): 213–14. http://dx.doi.org/10.1161/hypertensionaha.108.116129.
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Shabir, Saqib, William Cross, Lisa A. Kirkwood, Joanna F. Pearson, Peter A. Appleby, Dawn Walker, Ian Eardley, and Jennifer Southgate. "Functional expression of purinergic P2 receptors and transient receptor potential channels by the human urothelium." American Journal of Physiology-Renal Physiology 305, no. 3 (August 1, 2013): F396—F406. http://dx.doi.org/10.1152/ajprenal.00127.2013.
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In addition to its role as a physical barrier, the urothelium is considered to play an active role in mechanosensation. A key mechanism is the release of transient mediators that activate purinergic P2 receptors and transient receptor potential (TRP) channels to effect changes in intracellular Ca2+. Despite the implied importance of these receptors and channels in urothelial tissue homeostasis and dysfunctional bladder disease, little is known about their functional expression by the human urothelium. To evaluate the expression and function of P2X and P2Y receptors and TRP channels, the human ureter and bladder were used to separate urothelial and stromal tissues for RNA isolation and cell culture. RT-PCR using stringently designed primer sets was used to establish which P2 and TRP species were expressed at the transcript level, and selective agonists/antagonists were used to confirm functional expression by monitoring changes in intracellular Ca2+ and in a scratch repair assay. The results confirmed the functional expression of P2Y4 receptors and excluded nonexpressed receptors/channels (P2X1, P2X3, P2X6, P2Y6, P2Y11, TRPV5, and TRPM8), while a dearth of specific agonists confounded the functional validation of expressed P2X2, P2X4, P2Y1, P2Y2, TRPV2, TRPV3, TRPV6 and TRPM7 receptors/channels. Although a conventional response was elicited in control stromal-derived cells, the urothelial cell response to well-characterized TRPV1 and TRPV4 agonists/antagonists revealed unexpected anomalies. In addition, agonists that invoked an increase in intracellular Ca2+ promoted urothelial scratch repair, presumably through the release of ATP. The study raises important questions about the ligand selectivity of receptor/channel targets expressed by the urothelium. These pathways are important in urothelial tissue homeostasis, and this opens the possibility of selective drug targeting.
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Blythe, Sarah N., Jeremy F. Atherton, and Mark D. Bevan. "Synaptic Activation of Dendritic AMPA and NMDA Receptors Generates Transient High-Frequency Firing in Substantia Nigra Dopamine Neurons In Vitro." Journal of Neurophysiology 97, no. 4 (April 2007): 2837–50. http://dx.doi.org/10.1152/jn.01157.2006.
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Transient high-frequency activity of substantia nigra dopamine neurons is critical for striatal synaptic plasticity and associative learning. However, the mechanisms underlying this mode of activity are poorly understood because, in contrast to other rapidly firing neurons, high-frequency activity is not evoked by somatic current injection. Previous studies have suggested that activation of dendritic N-methyl-d-aspartate (NMDA) receptors and/or G-protein-coupled receptor (GPCR)-mediated reduction of action potential afterhyperpolarization and/or activation of cation channels underlie high-frequency activity. To address their relative contribution, transient high-frequency activity was evoked using local electrical stimulation (1 s, 10–100 Hz) in brain slices prepared from p15–p25 rats in the presence of GABA and D2 dopamine receptor antagonists. The frequency, pattern, and morphology of action potentials evoked under these conditions were similar to those observed in vivo. Evoked activity and reductions in action potential afterhyperpolarization were diminished greatly by application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or NMDA receptor selective antagonists and abolished completely by co-application of AMPA and NMDA antagonists. In contrast, application of glutamatergic and cholinergic GPCR antagonists moderately enhanced evoked activity. Dendritic pressure-pulse application of glutamate evoked high-frequency activity that was similarly sensitive to antagonism of AMPA or NMDA receptors. Taken together, these data suggest that dendritic AMPA and NMDA receptor-mediated synaptic conductances are sufficient to generate transient high-frequency activity in substantia nigra dopamine neurons by rapidly but transiently overwhelming the conductances underlying action potential afterhyperpolarization and/or engaging postsynaptic voltage-dependent ion channels in a manner that overcomes the limiting effects of afterhyperpolarization.
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Montell, Craig. "Drosophila sensory receptors—a set of molecular Swiss Army Knives." Genetics 217, no. 1 (January 1, 2021): 1–34. http://dx.doi.org/10.1093/genetics/iyaa011.
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Abstract Genetic approaches in the fruit fly, Drosophila melanogaster, have led to a major triumph in the field of sensory biology—the discovery of multiple large families of sensory receptors and channels. Some of these families, such as transient receptor potential channels, are conserved from animals ranging from worms to humans, while others, such as “gustatory receptors,” “olfactory receptors,” and “ionotropic receptors,” are restricted to invertebrates. Prior to the identification of sensory receptors in flies, it was widely assumed that these proteins function in just one modality such as vision, smell, taste, hearing, and somatosensation, which includes thermosensation, light, and noxious mechanical touch. By employing a vast combination of genetic, behavioral, electrophysiological, and other approaches in flies, a major concept to emerge is that many sensory receptors are multitaskers. The earliest example of this idea was the discovery that individual transient receptor potential channels function in multiple senses. It is now clear that multitasking is exhibited by other large receptor families including gustatory receptors, ionotropic receptors, epithelial Na+ channels (also referred to as Pickpockets), and even opsins, which were formerly thought to function exclusively as light sensors. Genetic characterizations of these Drosophila receptors and the neurons that express them also reveal the mechanisms through which flies can accurately differentiate between different stimuli even when they activate the same receptor, as well as mechanisms of adaptation, amplification, and sensory integration. The insights gleaned from studies in flies have been highly influential in directing investigations in many other animal models.
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Shen, Jian-Bing, Robin Shutt, Achilles Pappano, and Bruce T. Liang. "Characterization and mechanism of P2X receptor-mediated increase in cardiac myocyte contractility." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 5 (November 2007): H3056—H3062. http://dx.doi.org/10.1152/ajpheart.00515.2007.
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Cardiac P2X purinergic receptors can mediate an increase in myocyte contractility and a potentially important role in the heart. The P2X4 receptor (P2X4R) is an important subunit of native cardiac P2X receptors. With transgenic mice with cardiac-specific overexpression of P2X4R (Tg) used as a model, the objectives here were to characterize the P2X receptor-mediated cellular contractile and Ca2+ transient effects and to determine the mechanism underlying the receptor-induced increase in myocyte contractility. In response to the agonist 2-methylthioATP (2-meSATP), Tg myocytes showed an increased intracellular Ca2+ transient, as defined by fura 2 fluorescence ratio, and an enhanced contraction shortening that were unaccompanied by cAMP accumulation or L-type Ca2+ channel activation. The increased Ca2+ transient was not associated with any alteration in action potential duration, resting membrane potential, or diastolic fluorescence ratio or rates of rise and decline of the Ca2+ transient. Simultaneous Ca2+ transient and contraction measurements did not show any agonist-mediated change in myofilament Ca2+ sensitivity. However, activation of the overexpressed P2X4 receptor caused an enhanced SR Ca2+ loading, as evidenced by a 2-meSATP-evoked increase in the caffeine-induced inward current and Ca2+ transient. Similar data were obtained in wild-type mouse ventricular myocytes. Thus an increased SR Ca2+ content, occurring in the absence of cAMP accumulation or L-type Ca2+ channel activation, is the principal mechanism by which cardiac P2X receptor mediates a stimulatory effect on cardiac myocyte contractility.
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Pokkula, Swapna, and Santh Rani Thakur. "Icariin ameliorates partial sciatic nerve ligation induced neuropathic pain in rats: an evidence of in silico and in vivo studies." Journal of Pharmacy and Pharmacology 73, no. 7 (April 3, 2021): 874–80. http://dx.doi.org/10.1093/jpp/rgab021.
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Abstract Objectives Neuropathic pain (NP) is a chronic inflammation of the sciatic nerve, associated with complex pathophysiological events like neuronal ectopic discharge with changes in neurotransmitters, growth factors, receptors/ion channels including N-methyl-d-aspartate receptors, Transient receptor cation channels, Voltage-gated calcium channels. All these events eventually lead to inflammation and apoptosis of the sciatic nerve in NP. Icariin (ICA), a natural flavonoid is well known for its anti-inflammatory potential. Hence, the present study is designed to evaluate its anti-inflammatory potential against neuropathic pain using in silico and in vivo studies. Methods In silico studies were conducted using targets of N-methyl-D-aspartate receptor subtype-2B (NR2B), The capsaicin receptor transient receptor cation channel subfamily-V member-1 (TRPV1), N-type voltage-gated calcium (CaV2.2) channels. In in vivo studies, after partial sciatic nerve ligation surgery to animals, received their respective treatment for 21 days, further TNF-α, IL-6, Bax (proapoptotic) and Bcl-2 (antiapoptotic) expressions were estimated. Key findings ICA decreased the expressions of TNF-α, IL-6, Bax and increased expression of Bcl-2. In silico studies revealed a good energy binding score towards NR2B, TRPV1 receptors and CaV2.2 ion Channel. Conclusions ICA could be a promising agent in alleviating neuropathic pain by inhibiting NR2B, TRPV1 receptors and Cav2.2 channels, which induces anti-apoptotic potential and inhibits inflammation.
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Sugiyama, Daisuke, Sinyoung Kang, Nicholas Arpey, Preeyaphan Arunakul, Yuriy M. Usachev, and Timothy J. Brennan. "Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors." Anesthesiology 127, no. 4 (October 1, 2017): 695–708. http://dx.doi.org/10.1097/aln.0000000000001756.
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Abstract Background H2O2 has a variety of actions in skin wounds but has been rarely studied in deep muscle tissue. Based on response to the transient receptor potential ankyrin 1 antagonists after plantar incision, we hypothesized that H2O2 exerts nociceptive effects via the transient receptor potential ankyrin 1 in muscle. Methods Nociceptive behaviors in rats (n = 269) and mice (n = 16) were evaluated after various concentrations and volumes of H2O2 were injected into the gastrocnemius muscle or subcutaneous tissue. The effects of H2O2 on in vivo spinal dorsal horn neuronal activity and lumbar dorsal root ganglia neurons in vitro were evaluated from 26 rats and 6 mice. Results Intramuscular (mean ± SD: 1,436 ± 513 s) but not subcutaneous (40 ± 58 s) injection of H2O2 (100 mM, 0.6 ml) increased nociceptive time. Conditioned place aversion was evident after intramuscular (–143 ± 81 s) but not subcutaneous (–2 ± 111 s) injection of H2O2. These H2O2-induced behaviors were blocked by transient receptor potential ankyrin 1 antagonists. Intramuscular injection of H2O2 caused sustained in vivo activity of dorsal horn neurons, and H2O2 activated a subset of dorsal root ganglia neurons in vitro. Capsaicin nerve block decreased guarding after plantar incision and reduced nociceptive time after intramuscular H2O2. Nociceptive time after intramuscular H2O2 in transient receptor potential ankyrin 1 knockout mice was shorter (173 ± 156 s) compared with wild-type mice (931 ± 629 s). Conclusions The greater response of muscle tissue to H2O2 may help explain why incision that includes deep muscle but not skin incision alone produces spontaneous activity in nociceptive pathways.
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Tolhurst, Gwen, Catherine Vial, Catherine Léon, Christian Gachet, Richard J. Evans, and Martyn P. Mahaut-Smith. "Interplay between P2Y1, P2Y12, and P2X1 receptors in the activation of megakaryocyte cation influx currents by ADP: evidence that the primary megakaryocyte represents a fully functional model of platelet P2 receptor signaling." Blood 106, no. 5 (September 1, 2005): 1644–51. http://dx.doi.org/10.1182/blood-2005-02-0725.
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Abstract The difficulty of conducting electrophysiologic recordings from the platelet has restricted investigations into the role of ion channels in thrombosis and hemostasis. We now demonstrate that the well-established synergy between P2Y1 and P2Y12 receptors during adenosine diphosphate (ADP)–dependent activation of the platelet αIIbβ3 integrin also exists in murine marrow megakaryocytes, further supporting the progenitor cell as a bona fide model of platelet P2 receptor signaling. In patch clamp recordings, ADP (30 μM) stimulated a transient inward current at –70 mV, which was carried by Na+ and Ca2+ and was amplified by phenylarsine oxide, a potentiator of certain transient receptor potential (TRP) ion channels by phosphatidylinositol 4,5-bisphosphate depletion. This initial current decayed to a sustained phase, upon which repetitive transient inward cation currents with pre-dominantly P2X1-like kinetics were super-imposed. Abolishing P2X1-receptor activity prevented most of the repetitive currents, consistent with their activation by secreted adenosine triphosphate (ATP). Recordings in P2Y1-receptor–deficient megakaryocytes demonstrated an essential requirement of this receptor for activation of all ADP-evoked inward currents. However, P2Y12 receptors, through the activation of PI3-kinase, played a synergistic role in both P2Y1 and P2X1-receptor–dependent currents. Thus, direct stimulation of P2Y1 and P2Y12 receptors, together with autocrine P2X1 activation, is responsible for the activation of nonselective cation currents by the platelet agonistADP.
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Paik, Sang-Kyoo, Yeon-Kyung Na, and Yun-Sook Kim. "Characterization of Trigeminal Ganglion Neurons Expressing Transient Receptor Potential Ankyrin 1 (TRPA1) in the Rat." Korean Journal of Microscopy 42, no. 1 (March 31, 2012): 27–33. http://dx.doi.org/10.9729/am.2012.42.1.027.
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Ohashi, Nobuko, Daisuke Uta, Mika Sasaki, Masayuki Ohashi, Yoshinori Kamiya, and Tatsuro Kohno. "Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn." Anesthesiology 127, no. 2 (August 1, 2017): 355–71. http://dx.doi.org/10.1097/aln.0000000000001700.
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Abstract Background The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. Methods We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. Results Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 ± 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 ± 197.5 pA; N-acylphenolamine, 272.5 ± 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of Aδ-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naïve rats. Conclusions Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.
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Petrushenko, M. A., E. A. Petrushenko, and E. A. Lukyanetz. "STRUCTURE, PROPERTIES AND PHYSIOLOGICAL ROLE OF TRPA1 RECEPTORS." Fiziolohichnyĭ zhurnal 67, no. 1 (January 28, 2021): 44–56. http://dx.doi.org/10.15407/fz67.01.044.
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In mammals, the ankyrin ionotropic transient receptor potential type 1 (TRPA1) is the only member of the TRPA receptor gene subfamily. It is defined as a target for damaging and inflammatory effects in peripheral sensory neurons, which implies its functional role in the development of pain and neurogenic inflammation. Experimental studies indicate that calcium permeable non-selective ion receptor channel TRPA1 is activated by a number of exogenous irritant compounds, factors including low temperatures. This review describes the structure, properties, and physiological role of TRPA1 receptors.
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Tóth, Balázs I., Maik Konrad, Debapriya Ghosh, Florian Mohr, Christian R. Halaszovich, Michael G. Leitner, Joris Vriens, Johannes Oberwinkler, and Thomas Voets. "Regulation of the transient receptor potential channel TRPM3 by phosphoinositides." Journal of General Physiology 146, no. 1 (June 29, 2015): 51–63. http://dx.doi.org/10.1085/jgp.201411339.
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The transient receptor potential (TRP) channel TRPM3 is a calcium-permeable cation channel activated by heat and by the neurosteroid pregnenolone sulfate (PregS). TRPM3 is highly expressed in sensory neurons, where it plays a key role in heat sensing and inflammatory hyperalgesia, and in pancreatic β cells, where its activation enhances glucose-induced insulin release. However, despite its functional importance, little is known about the cellular mechanisms that regulate TRPM3 activity. Here, we provide evidence for a dynamic regulation of TRPM3 by membrane phosphatidylinositol phosphates (PIPs). Phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2) and ATP applied to the intracellular side of excised membrane patches promote recovery of TRPM3 from desensitization. The stimulatory effect of cytosolic ATP on TRPM3 reflects activation of phosphatidylinositol kinases (PI-Ks), leading to resynthesis of PIPs in the plasma membrane. Various PIPs directly enhance TRPM3 activity in cell-free inside-out patches, with a potency order PI(3,4,5)P3 > PI(3,5)P2 > PI(4,5)P2 ≈ PI(3,4)P2 >> PI(4)P. Conversely, TRPM3 activity is rapidly and reversibly inhibited by activation of phosphatases that remove the 5-phosphate from PIPs. Finally, we show that recombinant TRPM3, as well as the endogenous TRPM3 in insuloma cells, is rapidly and reversibly inhibited by activation of phospholipase C–coupled muscarinic acetylcholine receptors. Our results reveal basic cellular mechanisms whereby membrane receptors can regulate TRPM3 activity.
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Helyes, Zsuzsanna, Krisztián Elekes, József Németh, Gábor Pozsgai, Katalin Sándor, László Kereskai, Rita Börzsei, Erika Pintér, Árpád Szabó, and János Szolcsányi. "Role of transient receptor potential vanilloid 1 receptors in endotoxin-induced airway inflammation in the mouse." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 5 (May 2007): L1173—L1181. http://dx.doi.org/10.1152/ajplung.00406.2006.
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Airways are densely innervated by capsaicin-sensitive sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) receptors/ion channels, which play an important regulatory role in inflammatory processes via the release of sensory neuropeptides. The aim of the present study was to investigate the role of TRPV1 receptors in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity with functional, morphological, and biochemical techniques using receptor gene-deficient mice. Inflammation was evoked by intranasal administration of Escherichia coli lipopolysaccharide (60 μl, 167 μg/ml) in TRPV1 knockout (TRPV1−/−) mice and their wild-type counterparts (TRPV1+/+) 24 h before measurement. Airway reactivity was assessed by unrestrained whole body plethysmography, and its quantitative indicator, enhanced pause (Penh), was calculated after inhalation of the bronchoconstrictor carbachol. Histological examination and spectrophotometric myeloperoxidase measurement was performed from the lung. Somatostatin concentration was measured in the lung and plasma with radioimmunoassay. Bronchial hyperreactivity, histological lesions (perivascular/peribronchial edema, neutrophil/macrophage infiltration, goblet cell hyperplasia), and myeloperoxidase activity were significantly greater in TRPV−/− mice. Inflammation markedly elevated lung and plasma somatostatin concentrations in TRPV1+/+ but not TRPV1−/− animals. In TRPV1−/− mice, exogenous administration of somatostatin-14 (4 × 100 μg/kg ip) diminished inflammation and hyperreactivity. Furthermore, in wild-type mice, antagonizing somatostatin receptors by cyclo-somatostatin (4 × 250 μg/kg ip) increased these parameters. This study provides the first evidence for a novel counterregulatory mechanism during endotoxin-induced airway inflammation, which is mediated by somatostatin released from sensory nerve terminals in response to activation of TRPV1 receptors of the lung. It reaches the systemic circulation and inhibits inflammation and consequent bronchial hyperreactivity.
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Slaughter, M. M., and S. H. Bai. "Differential effects of baclofen on sustained and transient cells in the mudpuppy retina." Journal of Neurophysiology 61, no. 2 (February 1, 1989): 374–81. http://dx.doi.org/10.1152/jn.1989.61.2.374.
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1. Baclofen, a gamma-aminobutyric acid (GABA)/B receptor agonist, was bath applied while recording the responses of second- and third-order neurons in the mudpuppy retina. Baclofen receptors were largely restricted to amacrine and ganglion cells. 2. Baclofen hyperpolarized the membrane potential of many, but not all, third-order neurons. This involved an increase in input conductance, probably associated with an opening of potassium channels. 3. The maximal increase in input conductance associated with the activation of GABA/B receptors was approximately one-third of that produced by activation of GABA/A receptors. 4. Baclofen suppressed sustained responses but enhanced transient responses. The net effect was that responses throughout the inner retina became more transient in the presence of baclofen. 5. In sustained cells baclofen not only suppressed the sustained responses but also revealed large transient responses. Thus baclofen converted the light responses of these cells from sustained to transient. This suggests that sustained cells receive significant transient excitation which is normally masked by the sustained inputs. 6. The role of the GABA/B receptor in controlling response characteristics and information content of amacrine and ganglion cells is discussed.
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Kriszta, Gábor, Balázs Nemes, Zoltán Sándor, Péter Ács, Sámuel Komoly, Zoltán Berente, Kata Bölcskei, and Erika Pintér. "Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice." Cells 9, no. 1 (December 28, 2019): 81. http://dx.doi.org/10.3390/cells9010081.
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Transient receptor potential ankyrin 1 (TRPA1) receptors are non-selective cation channels responsive to a variety of exogenous irritants and endogenous stimuli including products of oxidative stress. It is mainly expressed by primary sensory neurons; however, expression of TRPA1 by astrocytes and oligodendrocytes has recently been detected in the mouse brain. Genetic deletion of TRPA1 was shown to attenuate cuprizone-induced oligodendrocyte apoptosis and myelin loss in mice. In the present study we aimed at investigating mGFAP-Cre conditional TRPA1 knockout mice in the cuprizone model. These animals were generated by crossbreeding GFAP-Cre+/− and floxed TRPA1 (TRPA1Fl/Fl) mice. Cuprizone was administered for 6 weeks and demyelination was followed by magnetic resonance imaging (MRI). At the end of the treatment, demyelination and glial activation was also investigated by histological methods. The results of the MRI showed that demyelination was milder at weeks 3 and 4 in both homozygous (GFAP-Cre+/− TRPA1Fl/Fl) and heterozygous (GFAP-Cre+/− TRPA1Fl/−) conditional knockout animals compared to Cre−/− control mice. However, by week 6 of the treatment the difference was not detectable by either MRI or histological methods. In conclusion, TRPA1 receptors on astrocytes may transiently contribute to the demyelination induced by cuprizone, however, expression and function of TRPA1 receptors by other cells in the brain (oligodendrocytes, microglia, neurons) warrant further investigation.
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Cohen, Ethan D. "Light-Evoked Excitatory Synaptic Currents of X-Type Retinal Ganglion Cells." Journal of Neurophysiology 83, no. 6 (June 1, 2000): 3217–29. http://dx.doi.org/10.1152/jn.2000.83.6.3217.
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The excitatory amino acid receptor (EAAR) types involved in the generation of light-evoked excitatory postsynaptic currents (EPSCs) were examined in X-type retinal ganglion cells. Using isolated and sliced preparations of cat and ferret retina, the light-evoked EPSCs of X cells were isolated by adding picrotoxin and strychnine to the bath to remove synaptic inhibition. N-methyl-d-aspartate (NMDA) receptors contribute significantly to the light-evoked EPSCs of on- andoff-X cells at many different holding potentials. An NMDA receptor contribution to the EPSCs was observable when retinal synaptic inhibition was either normally present or pharmacologically blocked. NMDA receptors formed 80% of the peak light-evoked EPSC at a holding potential of −40 mV; however, even at −80 mV, 20% of the light-evoked EPSC was NMDA-mediated. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor–mediated component to the light-evoked EPSCs predominated at a holding potential of −80 mV. The light-evoked EPSC was blocked by the AMPA receptor-selective antagonist GYKI52466 (50–100 μM). The AMPA receptor–mediated EPSC component had a linear current-voltage relation. AMPA receptors form the main non-NMDA EAAR current on bothon- and off- X ganglion cell dendrites. When synaptic transmission was blocked by the addition of Cd2+ to the Ringer, application of kainate directly to ganglion cells evoked excitatory currents that were strongly blocked by GYKI52466. Experiments using selective EAAR modulators showed the AMPA receptor–selective modulator cyclothiazide potentiated glutamate-evoked currents on X cells, while the kainate receptor–selective modulator concanavalin A (ConA) had no effect on kainate-evoked currents. Whereas the present study confirms the general notion that AMPA EAAR-mediated currents are transient and NMDA receptor–mediated currents are sustained, current-voltage relations of the light-evoked EPSC at different time points showed the contributions of these two receptor types significantly overlap. Both NMDA and AMPA EAARs can transmit transient and sustained visual signals in X ganglion cells, suggesting that much signal shaping occurs presynaptically in bipolar cells.
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Wagner, Thomas F. J., Sabine Loch, Sachar Lambert, Isabelle Straub, Stefanie Mannebach, Ilka Mathar, Martina Düfer, et al. "Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic β cells." Nature Cell Biology 10, no. 12 (November 2, 2008): 1421–30. http://dx.doi.org/10.1038/ncb1801.
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Tong, C. K., and M. Chesler. "Endogenous pH Shifts Facilitate Spreading Depression by Effect on NMDA Receptors." Journal of Neurophysiology 81, no. 4 (April 1, 1999): 1988–91. http://dx.doi.org/10.1152/jn.1999.81.4.1988.
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Endogenous pH shifts facilitate spreading depression by effect on NMDA receptors. Rapid extracellular alkalinizations accompany normal neuronal activity and have been implicated in the modulation of N-methyl-d-aspartate (NMDA) receptors. Particularly large alkaline transients also occur at the onset of spreading depression (SD). To test whether these endogenous pH shifts can modulate SD, the alkaline shift was amplified using benzolamide, a poorly permeant inhibitor of interstitial carbonic anhydrase. SD was evoked by microinjection of 1.2 M KCl into the CA1 stratum radiatum of rat hippocampal slices and recorded by a proximal double-barreled pH microelectrode and a distal potential electrode. In Ringer solution of pH 7.1 containing picrotoxin (but not at a bath pH of 7.4), addition of 10 μM benzolamide increased the SD alkaline shift from 0.20 ± 0.07 to 0.38 ± 0.17 unit pH (means ± SE). This was correlated with a significant shortening of the latency and an increase in the conduction velocity by 26 ± 16%. In the presence of the NMDA receptor antagonist dl−2-amino-5-phosphonovaleric acid (APV), benzolamide still amplified the alkaline transient, however, its effect on the SD latency and propagation velocity was abolished. The intrinsic modulation of SD by its alkaline transient may play an important role under focal ischemic conditions by removing the proton block of NMDA receptors where interstitial acidosis would otherwise limit NMDA receptor activity.
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Lin, You Shuei, Ruei-Lung Lin, Mauo-Ying Bien, Ching-Yin Ho, and Yu Ru Kou. "Sensitization of capsaicin-sensitive lung vagal afferents by anandamide in rats: role of transient receptor potential vanilloid 1 receptors." Journal of Applied Physiology 106, no. 4 (April 2009): 1142–52. http://dx.doi.org/10.1152/japplphysiol.91229.2008.
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Anandamide (AEA), an arachidonic acid derivative produced during inflammatory conditions, is an endogenous agonist of both transient receptor potential vanilloid 1 (TRPV1) receptors and cannabinoid CB1 receptors. Sensitization of capsaicin-sensitive lung vagal afferent (CSLVA) fibers by chemical mediators is important in the pathogenesis of hyperreactive airway diseases. We investigated the effect of the intravenous infusion of AEA (2 mg·kg−1·ml−1, 0.5 ml/min for 2 min) on the sensitivity of CSLVA fibers to chemical and mechanical stimulation in anesthetized rats. In artificially ventilated rats, AEA infusion only mildly elevated the baseline activity of CSLVA fibers. However, CSLVA fiber responses to right atrial injection of capsaicin, AEA, or adenosine and to lung inflation (tracheal pressure = 30 cmH2O) were all markedly potentiated during AEA infusion, which reverted 20 min after termination of the infusion. The potentiating effect on the sensitivity of CSLVA fibers to adenosine injection or lung inflation was completely blocked by pretreatment with capsazepine (a TRPV1 receptor antagonist) but was unaffected by pretreatment with AM281 (a CB1 receptor antagonist). In spontaneously breathing rats, right atrial injection of adenosine evoked an apneic response that is presumably mediated through CSLVA fibers. Similarly, the adenosine-evoked apneic response was potentiated during AEA infusion, and this potentiating effect was also completely prevented by pretreatment with capsazepine. These results suggest that AEA infusion at the dose tested produces a mild activation of TRPV1 receptors and this nonspecifically increases CSLVA fiber sensitivity to chemical and mechanical stimulation.
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Hsu, Wei-Lun, Hui-Wen Chung, Chih-Yueh Wu, Huei-Ing Wu, Yu-Tao Lee, En-Chan Chen, Weilun Fang, and Yen-Chung Chang. "Glutamate Stimulates Local Protein Synthesis in the Axons of Rat Cortical Neurons by Activating α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors and Metabotropic Glutamate Receptors." Journal of Biological Chemistry 290, no. 34 (July 1, 2015): 20748–60. http://dx.doi.org/10.1074/jbc.m115.638023.
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Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. By analyzing the metabolic incorporation of azidohomoalanine, a methionine analogue, in newly synthesized proteins, we find that glutamate treatments up-regulate protein translation not only in intact rat cortical neurons in culture but also in the axons emitting from cortical neurons before making synapses with target cells. The process by which glutamate stimulates local translation in axons begins with the binding of glutamate to the ionotropic AMPA receptors and metabotropic glutamate receptor 1 and members of group 2 metabotropic glutamate receptors on the plasma membrane. Subsequently, the activated mammalian target of rapamycin (mTOR) signaling pathway and the rise in Ca2+, resulting from Ca2+ influxes through calcium-permeable AMPA receptors, voltage-gated Ca2+ channels, and transient receptor potential canonical channels, in axons stimulate the local translation machinery. For comparison, the enhancement effects of brain-derived neurotrophic factor (BDNF) on the local protein synthesis in cortical axons were also studied. The results indicate that Ca2+ influxes via transient receptor potential canonical channels and activated the mTOR pathway in axons also mediate BDNF stimulation to local protein synthesis. However, glutamate- and BDNF-induced enhancements of translation in axons exhibit different kinetics. Moreover, Ca2+ and mTOR signaling appear to play roles carrying different weights, respectively, in transducing glutamate- and BDNF-induced enhancements of axonal translation. Thus, our results indicate that exposure to transient increases of glutamate and more lasting increases of BDNF would stimulate local protein synthesis in migrating axons en route to their targets in the developing brain.
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Zaccor, Nicholas W., Charlotte J. Sumner, and Solomon H. Snyder. "The nonselective cation channel TRPV4 inhibits angiotensin II receptors." Journal of Biological Chemistry 295, no. 29 (June 3, 2020): 9986–97. http://dx.doi.org/10.1074/jbc.ra120.014325.
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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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Brydon, Lena, Florian Roka, Laurence Petit, Pierre de Coppet, Michèle Tissot, Perry Barrett, Peter J. Morgan, Christian Nanoff, A. Donny Strosberg, and Ralf Jockers. "Dual Signaling of Human Mel1a Melatonin Receptors via Gi2, Gi3, and Gq/11 Proteins." Molecular Endocrinology 13, no. 12 (December 1, 1999): 2025–38. http://dx.doi.org/10.1210/mend.13.12.0390.
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Abstract Mel 1a melatonin receptors belong to the superfamily of guanine nucleotide-binding regulatory protein (G protein)-coupled receptors. So far, interest in Mel 1a receptor signaling has focused mainly on the modulation of the adenylyl cyclase pathway via pertussis toxin (PTX)-sensitive G proteins. To further investigate signaling of the human Mel 1a receptor, we have developed an antibody directed against the C terminus of this receptor. This antibody detected the Mel 1a receptor as a protein with an apparent molecular mass of approximately 60 kDa in immunoblots after separation by SDS-PAGE. It also specifically precipitated the 2-[125I]iodomelatonin (125I-Mel)-labeled receptor from Mel 1a-transfected HEK 293 cells. Coprecipitation experiments showed that Gi2, Gi3, and Gq/11 proteins couple to the Mel 1a receptor in an agonist-dependent and guanine nucleotide-sensitive manner. Coupling was selective since other G proteins present in HEK 293 cells, (Gi1, Go, Gs, Gz, and G12) were not detected in receptor complexes. Coupling of the Mel 1a receptor to Gi and Gq was confirmed by inhibition of high-affinity 125I-Mel binding to receptors with subtype-selective G protein α-subunit antibodies. Gi2 and/or Gi3 mediated adenylyl cyclase inhibition while Gq/11 induced a transient elevation in cytosolic calcium concentrations in HEK 293 cells stably expressing Mel 1a receptors. Melatonin-induced cytosolic calcium mobilization via PTX-insensitive G proteins was confirmed in primary cultures of ovine pars tuberalis cells endogenously expressing Mel 1a receptors. In conclusion, we report the development of the first antibody recognizing the cloned human Mel 1a melatonin receptor protein. We show that Mel 1a receptors functionally couple to both PTX-sensitive and PTX-insensitive G proteins. The previously unknown signaling of Mel 1a receptors through Gq/11 widens the spectrum of potential targets for melatonin.
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Stasiłowicz, Anna, Anna Tomala, Irma Podolak, and Judyta Cielecka-Piontek. "Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment." International Journal of Molecular Sciences 22, no. 2 (January 14, 2021): 778. http://dx.doi.org/10.3390/ijms22020778.
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Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson’s disease, Tourette’s syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood–brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.
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Naduchamy, Krishna P., and Varadarajan Parthasarathy. "A Review of the Potential Receptors of Migraine with a Special Emphasis on CGRP to Develop an Ideal Antimigraine Drug." Current Molecular Pharmacology 14, no. 1 (December 31, 2020): 11–26. http://dx.doi.org/10.2174/1874467213999200824124532.
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Background and Objective: Migraine is a neurovascular syndrome associated with unilateral, throbbing headache accompanied with nausea, vomiting and photo/phonophobia. Several proteins are involved in the etiopathogenesis of migraine headache. The aim of the present review is to give an insight into the various target proteins involved in migraine headache pertaining to the development of a potential anti-migraine drug molecule. Proteins/receptors such as serotonin (5-HT), Calcitonin Gene Related Peptide (CGRP), Transient Receptor Potential Vanilloid (TRPV1), cannabinoid, glutamate, opioid and histamine receptors play various roles in migraine. The nature of the proteins, their types, binding partner membrane proteins and the consequences of the reactions produced have been discussed. The studies conducted on animals and humans with the above mentioned target proteins/receptors and the results obtained have also been reviewed. Conclusion: Calcitonin Gene Related Peptide (CGRP), a G protein coupled receptor (GPCR) significantly contributed to the progression of migraine. CGRP antagonist inhibits the release of CGRP from trigeminal neurons of trigeminal ganglion. Based on the study results, the present review suggests that the inhibition of CGRP receptor might be a successful way to treat migraine headache. Currently, researchers across the world are focussing their attention towards the development of novel molecules to treat migraine headache by targeting CGRP receptor which can be attributed to its specificity among the several proteins involved in migraine.
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Yuan, Q., and T. Knöpfel. "Olfactory Nerve Stimulation-Evoked mGluR1 Slow Potentials, Oscillations, and Calcium Signaling in Mouse Olfactory Bulb Mitral Cells." Journal of Neurophysiology 95, no. 5 (May 2006): 3097–104. http://dx.doi.org/10.1152/jn.00001.2006.
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Fast synaptic transmission between olfactory receptor neurons and mitral cells (MCs) is mediated through AMPA and NMDA ionotropic glutamate receptors. MCs also express high levels of metabotropic glutamate receptor 1 (mGluR1) whose functional significance is less understood. Here we characterized a slow mGluR1-mediated potential that was evoked by high-frequency (100-Hz) olfactory nerve (ON) stimulation in the presence of NBQX and d-APV, blockers of ionotropic glutamate receptors, and that was associated with a local Ca2+ transient in the MC dendritic tuft. High-frequency ON stimulation in the presence of NBQX and d-APV also evoked a slow, nearly 2-Hz oscillation of MC membrane potential that was abolished by the mGluR1 antagonist LY367385 (50 μM). Both mGluR slow potential and slow oscillation persisted in the presence of gabazine (10 μM), a GABAA receptor antagonist, and intracellular QX-314 (10 mM), a Na+ channel blocker. In contrast to a slow mGluR1 potential in cerebellar Purkinje neurons, the MC mGluR1 potential was not depressed by SKF96365 (≤250 μM) and thus is likely not mediated by TRPC1 cation channels, nor was it potentiated by an elevation of intracellular Ca2+ level. Imaging with the Na+ indicator SBFI revealed a Na+ transient in the MC dendrite accompanying the mGluR1 slow potential. We conclude that the MC mGluR1 potential triggered by glutamate released from the ON supports oscillations and synchronizations of MCs associated within one glomerulus.
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Murad, John P., Harold J. Ting, and Fadi T. Khasawneh. "The Transient Receptor-Potential Channel 6 Plays a Critical Role In Platelet Function." Blood 116, no. 21 (November 19, 2010): 3201. http://dx.doi.org/10.1182/blood.v116.21.3201.3201.
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Abstract Abstract 3201 In spite of the fact that changes in the intracellular levels of calcium (e.g., calcium entry (CE)) is a central step in platelet activation, the underlying mechanism of this CE is still ill defined. Previous studies have demonstrated that of the transient receptor potential channel (TRPC) family, TRPC1 and, to a higher extent, TRPC6 are expressed in blood platelets, whereas TRPC4 is found in megakaryocytes (at the mRNA level). Furthermore, recent studies have shown that TRPC1 deficient platelets exhibited no defects in platelet function, and unaltered calcium homeostasis. Based on these considerations, we hypothesized that TRPC6 plays an essential role in receptor-operated calcium entry and platelet function. Our preliminary studies reveal that platelets deficient in TRPC6 exhibited a defect in platelet aggregation mediated by the thromboxane receptor (TPR), at least, at low agonist levels (i.e., low levels of receptor activation). Moreover, TRPC6 deficient mice also exhibited a significantly prolonged bleeding time, and were protected against thrombosis development, using a FeCl3 carotid-artery injury model. Together, these findings are consistent with the role of TPRs in hemostasis and the genesis of thrombosis. In future studies, we will investigate the role of TRPC6 in: 1. calcium homeostasis; 2. separate platelet functional responses such as dense granule secretion and shape change; and 3. in platelet activation via separate platelet G-protein coupled receptors such as PAR4 and P2Y1. These studies may define a new therapeutic target for managing multiple thrombosis-based disorders. Disclosures: No relevant conflicts of interest to declare.
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Vergnolle, Nathalie, Jessica Bertrand, Emilie D’Aldebert, and Corinne Rolland. "S3-4 H2S targets transient receptor potential receptors to relieve from inflammation and pain." Nitric Oxide 39 (May 2014): S4. http://dx.doi.org/10.1016/j.niox.2014.03.015.
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Yu, Hongmei, Qi Li, Victor P. Kolosov, Juliy M. Perelman, and Xiangdong Zhou. "Regulation of Particulate Matter-Induced Mucin Secretion by Transient Receptor Potential Vanilloid 1 Receptors." Inflammation 35, no. 6 (July 25, 2012): 1851–59. http://dx.doi.org/10.1007/s10753-012-9506-x.
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Sun, Hao, De-Pei Li, Shao-Rui Chen, Walter N. Hittelman, and Hui-Lin Pan. "Sensing of Blood Pressure Increase by Transient Receptor Potential Vanilloid 1 Receptors on Baroreceptors." Journal of Pharmacology and Experimental Therapeutics 331, no. 3 (September 2, 2009): 851–59. http://dx.doi.org/10.1124/jpet.109.160473.
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Fernandes, E. S., S. Awal, R. Karadaghi, and S. D. Brain. "TRP Receptors in Arthritis, Gaining Knowledge for Translation from Experimental Models." Open Pain Journal 6, no. 1 (March 8, 2013): 50–61. http://dx.doi.org/10.2174/1876386301306010050.
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Arthritis is a condition characterised by mainly pain, reduced joint movement and signs of inflammation, such as swelling. The disorder has many different types, of which osteoarthritis (a degenerative joint disease) and rheumatoid arthritis (a chronic autoimmune disease) are the two most common forms. There are >6 million sufferers in the UK and both conditions have a huge potential to impair capabilities and contribute to social and economic burdens. Whilst there are a wide range of arthritic therapies available, many patients under treatment complain of poor pain relief. Thus there is a need for novel therapeutic approaches, and the transient receptor potential (TRP) family of receptor channels has been investigated. One particular area of recent research has been the ligand-gated transient receptor potential vanilloid 1 (TRPV1) channel. Findings from numerous pre-clinical models and scientific studies have shown that TRPV1 desensitisation, or the use of TRPV1 antagonists alleviates pain and some inflammatory aspects. New findings have started to unveil the potential of other TRP channels in mediating arthritic pain and inflammation. With the understanding that the currently available treatments for arthritis are limited, researchers have looked into the exciting prospect that TRP receptor antagonists may be developed into effective, specific drugs, which would potentially protect against the complications of arthritis. These antagonists are still under development, although only data from studies from pre-clinical models are currently available. This review acts to summarize knowledge of the potential influence of TRP receptors in arthritis to date.
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Moriyama, Tomoko, Tohko Iida, Kimiko Kobayashi, Tomohiro Higashi, Tetsuo Fukuoka, Hideki Tsumura, Catherine Leon, et al. "Possible Involvement of P2Y2Metabotropic Receptors in ATP-Induced Transient Receptor Potential Vanilloid Receptor 1-Mediated Thermal Hypersensitivity." Journal of Neuroscience 23, no. 14 (July 9, 2003): 6058–62. http://dx.doi.org/10.1523/jneurosci.23-14-06058.2003.
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Ries, Craig R., Ray Pillai, Cheryl C. W. Chung, Jimmy T. C. Wang, Bernard A. MacLeod, and Stephan K. W. Schwarz. "QX-314 Produces Long-lasting Local Anesthesia Modulated by Transient Receptor Potential Vanilloid Receptors in Mice." Anesthesiology 111, no. 1 (July 1, 2009): 122–26. http://dx.doi.org/10.1097/aln.0b013e3181a9160e.
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Background The quaternary lidocaine derivative QX-314 is now known to produce long-lasting local anesthesia despite its positive charge. However, recent research suggests that the transient receptor potential vanilloid receptor agonist, capsaicin, should reduce the onset and offset times, whereas the transient receptor potential vanilloid receptor antagonist, capsazepine, should delay the onset time of sensory blockade by QX-314. Methods Sensory blockade in the tail of the conscious mouse was investigated using QX-314 2.5% in combination with capsaicin 0.1% and/or capsazepine (50 microg/ml). After tail injection, onset and offset times of local anesthesia were measured using the hot water tail-flick latency test. Results Capsaicin reduced the onset time of local anesthesia by QX-314 by more than 75% (Mann-Whitney test, P = 0.007; n = 10 per group) with no effect on the offset time of QX-314. For QX-314 without capsaicin, the onset and offset times were 23 min (interquartile range 15-30 min) and 300 min (interquartile range 285-375 min), respectively. For QX-314 with capsaicin, the onset and offset times were 4 min (interquartile range 3-8 min) and 360 min (interquartile range 285-435 min), respectively. In the antagonist study, capsazepine without added capsaicin decreased QX-314's efficacy, as 6 out of 9 mice did not develop sensory blockade after 90 min (Fisher exact test, P = 0.009). Conclusion We have confirmed in a sensory blockade model that QX-314 is a local anesthetic with a slow onset and a long duration of reversible blockade. Capsaicin, a transient receptor potential vanilloid receptor agonist, accelerated QX-314's onset kinetics, whereas capsazepine, a transient receptor potential vanilloid receptor antagonist, decreased QX-314's efficacy. These observations raise the possibility that endovanilloids may modulate cell entry of QX-314.
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WILLARS, Gary B., Craig A. McARDLE, and Stefan R. NAHORSKI. "Acute desensitization of phospholipase C-coupled muscarinic M3 receptors but not gonadotropin-releasing hormone receptors co-expressed in αT3-1 cells: implications for mechanisms of rapid desensitization." Biochemical Journal 333, no. 2 (July 15, 1998): 301–8. http://dx.doi.org/10.1042/bj3330301.
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In the present study we have expressed the muscarinic M3 receptor in an immortalized mouse pituitary cell line (αT3-1), which expresses an endogenous gonadotropin-releasing hormone (GnRH) receptor, to examine potential differences in acute receptor regulation. Both of these receptors couple to the activation of phosphoinositide-specific phospholipase C (PLC) in these cells and we demonstrate that, despite expression in the same cell background, acute desensitization is a feature of muscarinic M3 receptors but not of GnRH receptors. We show that, when the concentrations of GnRH and methacholine are matched to give approximately equivalent maximal elevations of Ins(1,4,5)P3, the GnRH receptor is able to sustain PLC activity at the initial rate, whereas the muscarinic M3 receptor cannot. Thus PLC-activating G-protein-coupled receptors are able to undergo rapid desensitization in this cell line, indicating that the desensitization profile is receptor-specific rather than cell-specific. This argues strongly that post-receptor regulatory features do not have a prominent role in mediating rapid desensitization in these cells. Furthermore GnRH receptor-mediated PLC activity is sustained despite a marked and persistent depletion in the steady-state level of PtdIns(4,5)P2. In contrast, activation of muscarinic receptors is not sustained despite only a transient decrease in PtdIns(4,5)P2 concentration. Thus, whereas the contribution of PtdIns(4,5)P2 depletion to the temporal profile of receptor-mediated PLC signalling has been difficult to assess, the present results demonstrate that this is unlikely to be of importance in these cells. We suggest that unique structural features of the GnRH receptor result in a lack of appropriate regulatory phospho-acceptor sites and that the absence of agonist-dependent phosphorylation might underlie the lack of acute regulation.
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Ramanathan, Sankari, Tatiana Tkatch, Jeremy F. Atherton, Charles J. Wilson, and Mark D. Bevan. "D2-Like Dopamine Receptors Modulate SKCa Channel Function in Subthalamic Nucleus Neurons Through Inhibition of Cav2.2 Channels." Journal of Neurophysiology 99, no. 2 (February 2008): 442–59. http://dx.doi.org/10.1152/jn.00998.2007.
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The activity patterns of subthalamic nucleus (STN) neurons are intimately related to motor function/dysfunction and modulated directly by dopaminergic neurons that degenerate in Parkinson's disease (PD). To understand how dopamine and dopamine depletion influence the activity of the STN, the functions/signaling pathways/substrates of D2-like dopamine receptors were studied using patch-clamp recording. In rat brain slices, D2-like dopamine receptor activation depolarized STN neurons, increased the frequency/irregularity of their autonomous activity, and linearized/enhanced their firing in response to current injection. Activation of D2-like receptors in acutely isolated neurons reduced transient outward currents evoked by suprathreshold voltage steps. Modulation was inhibited by a D2-like receptor antagonist and occluded by voltage-dependent Ca2+ (Cav) channel or small-conductance Ca2+-dependent K+ (SKCa) channel blockers or Ca2+-free media. Because Cav channels are targets of Gi/o-linked receptors, actions on step- and action potential waveform-evoked Cav channel currents were studied. D2-like receptor activation reduced the conductance of Cav2.2 but not Cav1 channels. Modulation was mediated, in part, by direct binding of Gβγ subunits because it was attenuated by brief depolarization. D2 and/or D3 dopamine receptors may mediate modulation because a D4-selective agonist was ineffective and mRNA encoding D2 and D3 but not D4 dopamine receptors was detectable. Brain slice recordings confirmed that SKCa channel-mediated action potential afterhyperpolarization was attenuated by D2-like dopamine receptor activation. Together, these data suggest that D2-like dopamine receptors potently modulate the negative feedback control of firing that is mediated by the functional coupling of Cav2.2 and SKCa channels in STN neurons.
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Cairns, B. E., J. Liu, and H. Wong. "Expression of α1 adrenergic receptor subtypes by afferent fibers that innervate rat masseter muscle." Scandinavian Journal of Pain 16, no. 1 (July 1, 2017): 167. http://dx.doi.org/10.1016/j.sjpain.2017.04.010.
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Abstract Aims In temporomandibular disorders sufferers, muscle pain is more severe in individuals who have undergone a traumatic stress. Why stress exacerbates masticatory muscle pain in these individuals is not known. One possibility is that under conditions of stress there is an interaction between the sympathetic and sensory nervous systems. This study investigated whether trigeminal ganglion neurons that innervate the masseter muscle express α1 adrenergic receptor subtypes to identify whether a direct interaction between the sympathetic and sensory nervous systems is feasible. Methods Masseter muscle ganglion neurons were identified by injection of the fluorescent dye fast blue into the masseter muscle of 4 Sprague Dawley rats (2 male, 2 female). Trigeminal ganglion sections were stained for α1a, α1b or α1d adrenergic receptors, as well as the transient receptor potential vanilloid 1 (TrpV1) receptor. Sections were examined with a Leica confocal microscope. The percent of masseter ganglion neurons expressing each receptor was calculated. Results Masseter muscle ganglion neurons expressed α1a(29 ± 9%), α1b (34 ± 4%) and α1d (19 ± 13%) adrenergic receptors. Expression of all three α1 receptor subtypes was higher in female rats than in male rats. Expression of α1b receptors was more commonly found on larger diameter masseter ganglion neurons. Overall 11±3% of masseter ganglion neurons expressed the TrpV1 receptor, which suggests they served a nociceptive function. The TrpV1 receptor was co-expressed by about ~10% of α1a and α1b receptor positive masseter ganglion neurons. Conclusions Afferent fibers that innervate the masseter muscle express all three α1 adrenergic receptor subtypes. Agonists at the α1 receptor have been previously shown to depolarize trigeminal ganglion neurons, which suggests that activation of these receptors on masseter muscle afferents would be excitatory. The expression of α1 receptors by putative nociceptors that innervate the masseter may permit a direct interaction between the sensory and sympathetic system that contributes to pain in this muscle.
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Wang, Hui, Donna H. Wang, and James J. Galligan. "P2Y2 receptors mediate ATP-induced resensitization of TRPV1 expressed by kidney projecting sensory neurons." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 298, no. 6 (June 2010): R1634—R1641. http://dx.doi.org/10.1152/ajpregu.00235.2009.
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The transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated cation channel expressed by sensory nerves. P2Y receptors are G protein-coupled receptors that are also expressed by TRPV1-positive sensory neurons. Therefore, we studied interactions between P2Y receptors and TRPV1 function on kidney projecting sensory neurons. Application of Fast Blue (FB) to nerves surrounding the renal artery retrogradely labeled neurons in dorsal root ganglia of rats. Whole cell recording was performed on FB-labeled neurons maintained in primary culture. Capsaicin was used to activate TRPV1. Four types of kidney projecting neurons were identified based on capsaicin responses: 1) desensitizing (35%), 2) nondesensitizing (29%), 3) silent (3%), and 4) insensitive (30%). Silent neurons responded to capsaicin only after ATP (100 μM) pretreatment. ATP reversed desensitization in desensitizing neurons. Insensitive neurons never responded to capsaicin. UTP, a P2Y purinoceptor 2 (P2Y2)/P2Y4 receptor agonist, reversed capsaicin-induced TRPV1 desensitization. 2-methyl-thio-ATP (2-Me-S-ATP), a P2Y1 receptor agonist, did not change desensitization. MRS 2179 and pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), drugs that block P2Y1 receptors, did not block ATP-induced resensitization of TRPV1. Suramin, a P2Y2 receptor antagonist, blocked resensitization caused by UTP. Immunocytochemical studies showed that FB-labeled neurons coexpressed P2Y2 receptors and TRPV1. We conclude that P2Y2 receptor activation can maintain TRPV1 function perhaps during sustained episodes of activity of kidney projecting sensory neurons.
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Wick, Elizabeth C., Steven G. Hoge, Sarah W. Grahn, Edward Kim, Lorna A. Divino, Eileen F. Grady, Nigel W. Bunnett, and Kimberly S. Kirkwood. "Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 5 (May 2006): G959—G969. http://dx.doi.org/10.1152/ajpgi.00154.2005.
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The mechanism of pancreatitis-induced pain is unknown. In other tissues, inflammation activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to liberate CGRP and substance P (SP) in peripheral tissues and the dorsal horn to cause neurogenic inflammation and pain, respectively. We evaluated the contribution of TRPV1, CGRP, and SP to pancreatic pain in rats. TRPV1, CGRP, and SP were coexpressed in nerve fibers of the pancreas. Injection of the TRPV1 agonist capsaicin into the pancreatic duct induced endocytosis of the neurokinin 1 receptor in spinal neurons in the dorsal horn (T10), indicative of SP release upon stimulation of pancreatic sensory nerves. Induction of necrotizing pancreatitis by treatment with l-arginine caused a 12-fold increase in the number of spinal neurons expressing the proto-oncogene c-fos in laminae I and II of L1, suggesting activation of nociceptive pathways. l-Arginine also caused a threefold increase in spontaneous abdominal contractions detected by electromyography, suggestive of referred pain. Systemic administration of the TRPV1 antagonist capsazepine inhibited c-fos expression by 2.5-fold and abdominal contractions by 4-fold. Intrathecal, but not systemic, administration of antagonists of CGRP (CGRP8–37) and SP (SR140333) receptors attenuated c-fos expression in spinal neurons by twofold. Thus necrotizing pancreatitis activates TRPV1 on pancreatic sensory nerves to release SP and CGRP in the dorsal horn, resulting in nociception. Antagonism of TRPV1, SP, and CGRP receptors may suppress pancreatitis pain.
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Rossi, Gianna, Beatrice Dufrusine, Anna Rita Lizzi, Carla Luzi, Alessandra Piccoli, Filomena Fezza, Roberto Iorio, et al. "Bisphenol A Deranges the Endocannabinoid System of Primary Sertoli Cells with an Impact on Inhibin B Production." International Journal of Molecular Sciences 21, no. 23 (November 26, 2020): 8986. http://dx.doi.org/10.3390/ijms21238986.
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Bisphenol A (BPA) is an endocrine disruptor that negatively affects spermatogenesis, a process where Sertoli cells play a central role. Thus, in the present study we sought to ascertain whether BPA could modulate the endocannabinoid (eCB) system in exposed mouse primary Sertoli cells. Under our experimental conditions, BPA turned out to be cytotoxic to Sertoli cells with an half-maximal inhibitory concentration (IC50) of ~6.0 µM. Exposure to a non-cytotoxic dose of BPA (i.e., 0.5 μM for 48 h) increased the expression levels of specific components of the eCB system, namely: type-1 cannabinoid (CB1) receptor and diacylglycerol lipase-α (DAGL-α), at mRNA level, type-2 cannabinoid (CB2) receptor, transient receptor potential vanilloid 1 (TRPV1) receptors, and DAGL-β, at protein level. Interestingly, BPA also increased the production of inhibin B, but not that of transferrin, and blockade of either CB2 receptor or TRPV1 receptor further enhanced the BPA effect. Altogether, our study provides unprecedented evidence that BPA deranges the eCB system of Sertoli cells towards CB2- and TRPV1-dependent signal transduction, both receptors being engaged in modulating BPA effects on inhibin B production. These findings add CB2 and TRPV1 receptors, and hence the eCB signaling, to the other molecular targets of BPA already known in mammalian cells.
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Shibukawa, Yoshiyuki, Masaki Sato, Maki Kimura, Ubaidus Sobhan, Miyuki Shimada, Akihiro Nishiyama, Aya Kawaguchi, et al. "Odontoblasts as sensory receptors: transient receptor potential channels, pannexin-1, and ionotropic ATP receptors mediate intercellular odontoblast-neuron signal transduction." Pflügers Archiv - European Journal of Physiology 467, no. 4 (June 18, 2014): 843–63. http://dx.doi.org/10.1007/s00424-014-1551-x.
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Feng, Nan-Hsiung, Hsang-Hsing Lee, Jeng-Chaun Shiang, and Ming-Chieh Ma. "Transient receptor potential vanilloid type 1 channels act as mechanoreceptors and cause substance P release and sensory activation in rat kidneys." American Journal of Physiology-Renal Physiology 294, no. 2 (February 2008): F316—F325. http://dx.doi.org/10.1152/ajprenal.00308.2007.
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Stimulation of capsaicin receptors results in an increase in afferent renal nerve activity (ARNA), but it is unclear how capsaicin contributes to sensory activation intrarenally. Here, we studied the relationships between capsaicin receptor activation, substance P (SP) release, and the sensory response in the rat renal pelvis. Immunoblots showed that one of the capsaicin receptors, transient receptor potential vanilloid type 1 channel (TRPV1), was found in various renal tissues and was especially abundant in the renal pelvis, where most sensory nerve fibers originate. Interestingly, immunolabeling showed colocalization of TRPV1, SP, and the panneuronal marker PGP9.5 in the renal pelvis. Electrophysiological recordings showed that SP and capsaicin activated the same mechanosensitive ARNA in a single-unit preparation. Intrapelvic administration of capsaicin or a specific TRPV1 agonist, resiniferatoxin, resulted in a dose-dependent increase in multi-unit ARNA and SP release, and these effects were blocked by the TRVP1 blocker capsazepine. Inhibition of the SP receptor by L-703,606 largely prevented capsaicin- or resiniferatoxin-induced ARNA. Capsazepine also prevented intrapelvic pressure (IPP)-dependent ARNA activation and contralateral diuresis/natriuresis in the renorenal reflex at an IPP of 20 mmHg, but had no effect at an IPP of 50 mmHg. These data indicate that TRPV1, a low-pressure baroreceptor, is present in the renal pelvis and exclusively regulates neuropeptide release from primary renal afferent C-fibers in response to mechanostimulation.
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Kojima, Akiko, Hirotoshi Kitagawa, Mariko Omatsu-Kanbe, Hiroshi Matsuura, and Shuichi Nosaka. "Sevoflurane Protects Ventricular Myocytes from Ca2+Paradox-mediated Ca2+Overload by Blocking the Activation of Transient Receptor Potential Canonical Channels." Anesthesiology 115, no. 3 (September 1, 2011): 509–22. http://dx.doi.org/10.1097/aln.0b013e31822b7901.
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Background Volatile anesthetics produce cardioprotective action by attenuating cellular Ca2+ overload. The Ca2+ paradox is an important model for studying the mechanisms associated with Ca2+ overload-mediated myocardial injury, and was recently found to be mediated by Ca2+ entry through the transient receptor potential canonical channels upon Ca2+ repletion. This study investigated the effect of sevoflurane on cellular mechanisms underlying the Ca2+ paradox. Methods The Ca2+ paradox was examined in fluo-3 or mag-fluo-4-loaded mouse ventricular myocytes using confocal laser scanning microscope, upon Ca2+ repletion after 15 min of Ca2+ depletion in the absence and presence of sevoflurane. Results The Ca2+ paradox was evoked in approximately 65% of myocytes upon Ca2+ repletion, as determined by an abrupt elevation of cytosolic Ca2+ accompanied by hypercontracture. The Ca2+ paradox was significantly suppressed by sevoflurane administered for 3 min before and during Ca2+ repletion (Post) or during Ca2+ depletion and repletion (Postlong), and Postlong was more beneficial than Post application. The sarcoplasmic reticulum Ca2+ levels gradually decreased during Ca2+ depletion, and the Ca2+ paradox was readily evoked in myocytes with reduced sarcoplasmic reticulum Ca2+ levels. Postlong but not Post application of sevoflurane prevented decrease in sarcoplasmic reticulum Ca2+ levels by blocking Ca2+ leak through ryanodine receptors. Whole cell patch-clamp recordings revealed that sevoflurane rapidly blocked thapsigargin-induced transient receptor potential canonical currents. Conclusions Sevoflurane protects ventricular myocytes from Ca2+ paradox-mediated Ca2+ overload by blocking transient receptor potential canonical channels and by preventing the decrease in sarcoplasmic reticulum Ca2+ levels, which is associated with less activation of transient receptor potential canonical channels.
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Camilleri, Michael. "Toward an effective peripheral visceral analgesic: responding to the national opioid crisis." American Journal of Physiology-Gastrointestinal and Liver Physiology 314, no. 6 (June 1, 2018): G637—G646. http://dx.doi.org/10.1152/ajpgi.00013.2018.
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This mini-review summarizes recent new developments in visceral analgesics. This promising field is important, as a new approach to address abdominal pain with peripheral visceral analgesics is considered a key approach to addressing the current opioid crisis. Some of the novel compounds address peripheral pain mechanisms through modulation of opioid receptors via biased ligands, nociceptin/orphanin FQ opioid peptide (NOP) receptor, or dual action on NOP and μ-opioid receptor, buprenorphine and morphiceptin analogs. Other compounds target nonopioid mechanisms, including cannabinoid (CB2), N-methyl-d-aspartate, calcitonin gene-related peptide, estrogen, and adenosine A2B receptors and transient receptor potential (TRP) channels (TRPV1, TRPV4, and TRPM8). Although current evidence is based predominantly on animal models of visceral pain, early human studies also support the evidence from the basic and animal research. This augurs well for the development of nonaddictive, visceral analgesics for treatment of chronic abdominal pain, an unmet clinical need.
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Fuenzalida, Marco, David Fernández de Sevilla, Alejandro Couve, and Washington Buño. "Role of AMPA and NMDA Receptors and Back-Propagating Action Potentials in Spike Timing–Dependent Plasticity." Journal of Neurophysiology 103, no. 1 (January 2010): 47–54. http://dx.doi.org/10.1152/jn.00416.2009.
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The cellular mechanisms that mediate spike timing–dependent plasticity (STDP) are largely unknown. We studied in vitro in CA1 pyramidal neurons the contribution of AMPA and N-methyl-d-aspartate (NMDA) components of Schaffer collateral (SC) excitatory postsynaptic potentials (EPSPs; EPSPAMPA and EPSPNMDA) and of the back-propagating action potential (BAP) to the long-term potentiation (LTP) induced by a STDP protocol that consisted in pairing an EPSP and a BAP. Transient blockade of EPSPAMPA with 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX) during the STDP protocol prevented LTP. Contrastingly LTP was induced under transient inhibition of EPSPAMPA by combining SC stimulation, an imposed EPSPAMPA-like depolarization, and BAP or by coupling the EPSPNMDA evoked under sustained depolarization (approximately −40 mV) and BAP. In Mg2+-free solution EPSPNMDA and BAP also produced LTP. Suppression of EPSPNMDA or BAP always prevented LTP. Thus activation of NMDA receptors and BAPs are needed but not sufficient because AMPA receptor activation is also obligatory for STDP. However, a transient depolarization of another origin that unblocks NMDA receptors and a BAP may also trigger LTP.
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Assimakopoulou, Martha, Dionysios Pagoulatos, Pinelopi Nterma, and Nikolaos Pharmakakis. "Immunolocalization of cannabinoid receptor type 1 and CB2 cannabinoid receptors, and transient receptor potential vanilloid channels in pterygium." Molecular Medicine Reports 16, no. 4 (August 14, 2017): 5285–93. http://dx.doi.org/10.3892/mmr.2017.7246.
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