Journal articles on the topic 'GPCR-TRP channel'
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1
Tatsumi, Manae, Takayuki Kishi, Satoru Ishida, Hiroki Kawana, Akiharu Uwamizu, Yuki Ono, Kouki Kawakami, Junken Aoki, and Asuka Inoue. "Ectodomain shedding of EGFR ligands serves as an activation readout for TRP channels." PLOS ONE 18, no. 1 (January 20, 2023): e0280448. http://dx.doi.org/10.1371/journal.pone.0280448.
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Transient receptor potential (TRP) channels are activated by various extracellular and intracellular stimuli and are involved in many physiological events. Because compounds that act on TRP channels are potential candidates for therapeutic agents, a simple method for evaluating TRP channel activation is needed. In this study, we demonstrated that a transforming growth factor alpha (TGFα) shedding assay, previously developed for detecting G-protein–coupled receptor (GPCR) activation, can also detect TRP channel activation. This assay is a low-cost, easily accessible method that requires only an absorbance microplate reader. Mechanistically, TRP-channel-triggered TGFα shedding is achieved by both of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and 17 (ADAM17), whereas the GPCR-induced TGFα shedding response depends solely on ADAM17. This difference may be the result of qualitative or quantitative differences in intracellular Ca2+ kinetics between TRP channels and GPCRs. Use of epidermal growth factor (EGF) and betacellulin (BTC), substrates of ADAM10, improved the specificity of the shedding assay by reducing background responses mediated by endogenously expressed GPCRs. This assay for TRP channel measurement will not only facilitate the high-throughput screening of TRP channel ligands but also contribute to understanding the roles played by TRP channels as regulators of membrane protein ectodomain shedding.
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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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Yekkirala, Ajay S. "Two to tango: GPCR oligomers and GPCR-TRP channel interactions in nociception." Life Sciences 92, no. 8-9 (March 2013): 438–45. http://dx.doi.org/10.1016/j.lfs.2012.06.021.
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Oronowicz, Jakub, Jacqueline Reinhard, Peter Sol Reinach, Szymon Ludwiczak, Huan Luo, Marah Hussain Omar Ba Salem, Miriam Monika Kraemer, Heike Biebermann, Vinodh Kakkassery, and Stefan Mergler. "Ascorbate-induced oxidative stress mediates TRP channel activation and cytotoxicity in human etoposide-sensitive and -resistant retinoblastoma cells." Laboratory Investigation 101, no. 1 (September 18, 2020): 70–88. http://dx.doi.org/10.1038/s41374-020-00485-2.
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AbstractThere are indications that pharmacological doses of ascorbate (Asc) used as an adjuvant improve the chemotherapeutic management of cancer. This favorable outcome stems from its cytotoxic effects due to prooxidative mechanisms. Since regulation of intracellular Ca2+ levels contributes to the maintenance of cell viability, we hypothesized that one of the effects of Asc includes disrupting regulation of intracellular Ca2+ homeostasis. Accordingly, we determined if Asc induced intracellular Ca2+ influx through activation of pertussis sensitive Gi/o-coupled GPCR which in turn activated transient receptor potential (TRP) channels in both etoposide-resistant and -sensitive retinoblastoma (WERI-Rb1) tumor cells. Ca2+ imaging, whole-cell patch-clamping, and quantitative real-time PCR (qRT-PCR) were performed in parallel with measurements of RB cell survival using Trypan Blue cell dye exclusion. TRPM7 gene expression levels were similar in both cell lines whereas TRPV1, TRPM2, TRPA1, TRPC5, TRPV4, and TRPM8 gene expression levels were downregulated in the etoposide-resistant WERI-Rb1 cells. In the presence of extracellular Ca2+, 1 mM Asc induced larger intracellular Ca2+ transients in the etoposide-resistant WERI-Rb1 than in their etoposide-sensitive counterpart. With either 100 µM CPZ, 500 µM La3+, 10 mM NAC, or 100 µM 2-APB, these Ca2+ transients were markedly diminished. These inhibitors also had corresponding inhibitory effects on Asc-induced rises in whole-cell currents. Pertussis toxin (PTX) preincubation blocked rises in Ca2+ influx. Microscopic analyses showed that after 4 days of exposure to 1 mM Asc cell viability fell by nearly 100% in both RB cell lines. Taken together, one of the effects underlying oxidative mediated Asc-induced WERI-Rb1 cytotoxicity stems from its promotion of Gi/o coupled GPCR mediated increases in intracellular Ca2+ influx through TRP channels. Therefore, designing drugs targeting TRP channel modulation may be a viable approach to increase the efficacy of chemotherapeutic treatment of RB. Furthermore, Asc may be indicated as a possible supportive agent in anti-cancer therapies.
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Tsiokas, Leonidas. "Function and regulation of TRPP2 at the plasma membrane." American Journal of Physiology-Renal Physiology 297, no. 1 (July 2009): F1—F9. http://dx.doi.org/10.1152/ajprenal.90277.2008.
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The vast majority (∼99%) of all known cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by naturally occurring mutations in two separate, but genetically interacting, loci, pkd1 and pkd2. pkd1 encodes a large multispanning membrane protein (PKD1) of unknown function, while pkd2 encodes a protein (TRPP2, polycystin-2, or PKD2) of the transient receptor potential (TRP) superfamily of ion channels. Biochemical, functional, and genetic studies support a model in which PKD1 physically interacts with TRPP2 to form an ion channel complex that conveys extracellular stimuli to ionic currents. However, the molecular identity of these extracellular stimuli remains elusive. Functional studies in cell culture show that TRPP2 can be activated in response to mechanical cues (fluid shear stress) and/or receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) activation at the cell surface. Recent genetic studies in Chlamydomonas reinhardtii show that CrPKD2 functions in a pathway linking cell-cell adhesion and Ca2+ signaling. The mode of activation depends on protein-protein interactions with other channel subunits and auxiliary proteins. Therefore, understanding the mechanisms underlying the molecular makeup of TRPP2-containing complexes is critical in delineating the mechanisms of TRPP2 activation and, most importantly, the mechanisms by which naturally occurring mutations in pkd1 or pkd2 lead not only to ADPKD, but also to other defects reported in model organisms lacking functional TRPP2. This review focuses on the molecular assembly, function, and regulation of TRPP2 as a cell surface cation channel and discusses its potential role in Ca2+ signaling and ADPKD pathophysiology.
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Liu, Fangzhou, Yuanbai Li, Meng Li, Jing Wang, Yiying Zhang, Yu Du, and Yang Yang. "Study on Mechanism of Iridoid Glycosides Derivatives from Fructus Gardeniae in Jiangxi Province by Network Pharmacology." Evidence-Based Complementary and Alternative Medicine 2020 (June 27, 2020): 1–12. http://dx.doi.org/10.1155/2020/4062813.
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Objective. To investigate the pharmacological mechanism of the iridoid glycosides from Fructus Gardeniae in Jiangxi province by network pharmacology. To provide a valuable research strategy for the rational use and in-depth research and development of Fructus Gardeniae from Jiangxi. Method. Previous research results of our group show that the contents of iridoid glycosides in Fructus Gardeniae from Jiangxi province have a significant difference compared with other regions (P<0.05). Based on our previous experimental results, this study selected six characteristic high-content bioactive iridoid glycosides components of Fructus Gardeniae from Jiangxi province as candidate components. TCMSP database was used to obtain the process parameters of absorption, distribution, metabolism, and excretion (ADME) of candidate components. PubChem and SWISS online database were used to predict the related targets. Cytoscape software was used to the construct compound-target-disease (C-T-D) network of the Fructus Gardeniae iridoid glycosides ingredients. Furthermore, the GO biological process analysis and the pathway enrichment analysis were carried out using the CTD online analysis platform; then, an illustrated network that contains the main “chemicals-targets-pathway (C-T-P)” was constructed to analyze main biological pathways for obtaining the deep mechanism of Fructus Gardeniae in Jiangxi. Results. 6 iridoid glycosides, namely geniposide, gardenoside, geniposidic acid, genipin 1-gentiobioside, gardoside, and shanzhiside, from Fructus Gardeniae in Jiangxi province were obtained as candidate components through previous work and network pharmacology screening. 36 corresponding targets were acted, such as BCL2, MAPT, F2, BCL2L1, PRKCD, PRKCB, HIF1A, and PRKCA. These targets could joint in pathways, such as signaling by GPCR, neuroactive ligand-receptor interaction, inflammatory mediator regulation of TRP channels, and ion channel transport. Interestingly, these pathways were highly associated with liver diseases, neurological diseases, hypertension, neoplasms, hyperalgesia, and inflammation. Remarkably, we boldly speculate that the Fructus Gardeniae from Jiangxi province can play a pharmacological role in hepatic encephalopathy through regulating multiple signaling pathways in an integrated manner. Conclusion. The method based on system pharmacology could help to find the key targets of characteristic high-content chemical constituents of herb from different producing areas, the signaling pathway and disease network of TCM, and provide useful information and data support for giving a further study on traditional Chinese medicine resources in different regions of China.
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Kukkonen, J. P. "International symposium on G-protein-coupled receptors (GPCRs), TRP (ion) channels and lipid signalling - GPCR-Helsinki 2010." Acta Physiologica 204, no. 2 (January 4, 2012): 148–50. http://dx.doi.org/10.1111/j.1748-1716.2011.02393.x.
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Hariharan, Ashwini, Nick Weir, Colin Robertson, Liqun He, Christer Betsholtz, and Thomas A. Longden. "The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes." Frontiers in Cellular Neuroscience 14 (December 18, 2020). http://dx.doi.org/10.3389/fncel.2020.601324.
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Brain pericytes reside on the abluminal surface of capillaries, and their processes cover ~90% of the length of the capillary bed. These cells were first described almost 150 years ago (Eberth, 1871; Rouget, 1873) and have been the subject of intense experimental scrutiny in recent years, but their physiological roles remain uncertain and little is known of the complement of signaling elements that they employ to carry out their functions. In this review, we synthesize functional data with single-cell RNAseq screens to explore the ion channel and G protein-coupled receptor (GPCR) toolkit of mesh and thin-strand pericytes of the brain, with the aim of providing a framework for deeper explorations of the molecular mechanisms that govern pericyte physiology. We argue that their complement of channels and receptors ideally positions capillary pericytes to play a central role in adapting blood flow to meet the challenge of satisfying neuronal energy requirements from deep within the capillary bed, by enabling dynamic regulation of their membrane potential to influence the electrical output of the cell. In particular, we outline how genetic and functional evidence suggest an important role for Gs-coupled GPCRs and ATP-sensitive potassium (KATP) channels in this context. We put forth a predictive model for long-range hyperpolarizing electrical signaling from pericytes to upstream arterioles, and detail the TRP and Ca2+ channels and Gq, Gi/o, and G12/13 signaling processes that counterbalance this. We underscore critical questions that need to be addressed to further advance our understanding of the signaling topology of capillary pericytes, and how this contributes to their physiological roles and their dysfunction in disease.
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Patel, Atit A., Akira Sakurai, Nathaniel J. Himmel, and Daniel N. Cox. "Modality specific roles for metabotropic GABAergic signaling and calcium induced calcium release mechanisms in regulating cold nociception." Frontiers in Molecular Neuroscience 15 (September 9, 2022). http://dx.doi.org/10.3389/fnmol.2022.942548.
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Calcium (Ca2+) plays a pivotal role in modulating neuronal-mediated responses to modality-specific sensory stimuli. Recent studies in Drosophila reveal class III (CIII) multidendritic (md) sensory neurons function as multimodal sensors regulating distinct behavioral responses to innocuous mechanical and nociceptive thermal stimuli. Functional analyses revealed CIII-mediated multimodal behavioral output is dependent upon activation levels with stimulus-evoked Ca2+ displaying relatively low vs. high intracellular levels in response to gentle touch vs. noxious cold, respectively. However, the mechanistic bases underlying modality-specific differential Ca2+ responses in CIII neurons remain incompletely understood. We hypothesized that noxious cold-evoked high intracellular Ca2+ responses in CIII neurons may rely upon Ca2+ induced Ca2+ release (CICR) mechanisms involving transient receptor potential (TRP) channels and/or metabotropic G protein coupled receptor (GPCR) activation to promote cold nociceptive behaviors. Mutant and/or CIII-specific knockdown of GPCR and CICR signaling molecules [GABAB-R2, Gαq, phospholipase C, ryanodine receptor (RyR) and Inositol trisphosphate receptor (IP3R)] led to impaired cold-evoked nociceptive behavior. GPCR mediated signaling, through GABAB-R2 and IP3R, is not required in CIII neurons for innocuous touch evoked behaviors. However, CICR via RyR is required for innocuous touch-evoked behaviors. Disruptions in GABAB-R2, IP3R, and RyR in CIII neurons leads to significantly lower levels of cold-evoked Ca2+ responses indicating GPCR and CICR signaling mechanisms function in regulating Ca2+ release. CIII neurons exhibit bipartite cold-evoked firing patterns, where CIII neurons burst during rapid temperature change and tonically fire during steady state cold temperatures. GABAB-R2 knockdown in CIII neurons resulted in disorganized firing patterns during cold exposure. We further demonstrate that application of GABA or the GABAB specific agonist baclofen potentiates cold-evoked CIII neuron activity. Upon ryanodine application, CIII neurons exhibit increased bursting activity and with CIII-specific RyR knockdown, there is an increase in cold-evoked tonic firing and decrease in bursting. Lastly, our previous studies implicated the TRPP channel Pkd2 in cold nociception, and here, we show that Pkd2 and IP3R genetically interact to specifically regulate cold-evoked behavior, but not innocuous mechanosensation. Collectively, these analyses support novel, modality-specific roles for metabotropic GABAergic signaling and CICR mechanisms in regulating intracellular Ca2+ levels and cold-evoked behavioral output from multimodal CIII neurons.
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Blaho, Victoria, Jerold Chun, Aaron Frantz, Timothy Hla, Danielle Jones, Deepa Jonnalagadda, Yasuyuki Kihara, et al. "Lysophospholipid (LPA) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database." IUPHAR/BPS Guide to Pharmacology CITE 2019, no. 4 (September 16, 2019). http://dx.doi.org/10.2218/gtopdb/f36/2019.4.
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Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [50, 18]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [38], leading to deorphanisation of members of the endothelial differentiation gene (edg) family as other LPA receptors along with sphingosine 1-phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as LPAR1, etc. to reflect the receptor function of proteins. The crystal structure of LPA1 was solved and demonstrates extracellular LPA access to the binding pocket, consistent with proposed delivery via autotaxin [12]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Binding affinities of unlabeled, natural LPA and AEAp to LPA1 were measured using backscattering interferometry (pKd = 9) [73]. Binding affinities were 77-fold lower than than values obtained using radioactivity [111]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out via a novel TGFα "shedding" assay [45]. LPA has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [76] and TRPA1 [53]. LPA was originally proposed to be a ligand for GPCR35, but data show that in fact it is a receptor for CXCL17 [68]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.
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Blaho, Victoria, Jerold Chun, Danielle Jones, Deepa Jonnalagadda, Yasuyuki Kihara, Wouter Moolenaar, Tony Ngo, Manisha Ray, and Valerie Tan. "Lysophospholipid (LPA) receptors (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database." IUPHAR/BPS Guide to Pharmacology CITE 2020, no. 5 (November 12, 2020). http://dx.doi.org/10.2218/gtopdb/f36/2020.5.
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Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [54, 18, 80, 125]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [39], leading to deorphanisation of members of the endothelial differentiation gene (edg) family as other LPA receptors along with sphingosine 1-phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as LPAR1, etc. to reflect the receptor function of proteins. The crystal structure of LPA1 was solved and demonstrates extracellular LPA access to the binding pocket, consistent with proposed delivery via autotaxin [12]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Binding affinities of unlabeled, natural LPA and AEAp to LPA1 were measured using backscattering interferometry (pKd = 9) [81, 102]. Binding affinities were 77-fold lower than than values obtained using radioactivity [124]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out via a novel TGFα "shedding" assay [47]. LPA LPA has been proposed to be a ligand for GPCR35 [92], supported by a recent study revealing that LPA modulates macrophage function through GPR35 [53]. However CXCL17 is reported to be a ligand for GPR35/CXCR8 [74]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [85] and TRPA1 [57]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.
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Quallo, Talisia, Omar Alkhatib, Clive Gentry, David A. Andersson, and Stuart Bevan. "G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons." eLife 6 (August 15, 2017). http://dx.doi.org/10.7554/elife.26138.
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Transient receptor potential (TRP) ion channels in peripheral sensory neurons are functionally regulated by hydrolysis of the phosphoinositide PI(4,5)P2 and changes in the level of protein kinase mediated phosphorylation following activation of various G protein coupled receptors. We now show that the activity of TRPM3 expressed in mouse dorsal root ganglion (DRG) neurons is inhibited by agonists of the Gi-coupled µ opioid, GABA-B and NPY receptors. These agonist effects are mediated by direct inhibition of TRPM3 by Gβγ subunits, rather than by a canonical cAMP mediated mechanism. The activity of TRPM3 in DRG neurons is also negatively modulated by tonic, constitutive GPCR activity as TRPM3 responses can be potentiated by GPCR inverse agonists. GPCR regulation of TRPM3 is also seen in vivo where Gi/o GPCRs agonists inhibited and inverse agonists potentiated TRPM3 mediated nociceptive behavioural responses.
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Van Giel, Dorien, Jean-Paul Decuypere, Djalila Mekahli, and Rudi Vennekens. "MO007ANALYSIS OF CALCIUM SIGNALING IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)." Nephrology Dialysis Transplantation 36, Supplement_1 (May 1, 2021). http://dx.doi.org/10.1093/ndt/gfab079.003.
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Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inheritable kidney disease characterized by the development of fluid-filled cysts in all nephron segments, leading to loss of renal function. Mutations in PKD1 or PKD2, which encode polycystin-1 and polycystin-2, are the most common cause of ADPKD. The molecular mechanisms underlying cystogenesis are poorly characterized but it is postulated that disturbed calcium homeostasis is a primary event in cystogenesis. The precise molecular players that cause this disturbance are still a poorly explored area, especially in relevant human cell types. We therefore aim to characterize the profile of calcium-coupled receptors and channels in a human renal epithelial cell model, to identify which receptors and channels are present and whether their function is affected in ADPKD. Method Human urine-derived conditionally immortalized proximal tubule epithelial cells (ciPTECs) of ADPKD patients and healthy controls were screened for calcium-coupled GPCRs, using a GPCR agonist library on Fura-2 loaded cell populations seeded in 96-well format using the Flexstation3 (Molecular Devices). Validation of specific hits was done using single-cell measurements with a fluorescence microscope and built-in perfusion system. The expression of TRP channels and STIM/Orai proteins was determined via qPCR. Results From a library of 418 GPCR agonists a selective amount of calcium-coupled GPCRs was found functionally active in ciPTECs. ciPTECs from both healthy controls and ADPKD patients were found to functionally express purinergic -, histamine -, serotonin and dopamine receptors. Through qPCR we found expression of various TRP channels, including TRPML1, TRPC1/3, TRPM3/4/7, TRPV4 and TRPA1, as well as high expression of STIM1/2 and Orai1/2/3. Conclusion We describe the first thorough characterization of molecular players involved in calcium signalling mechanisms in human renal epithelial cells, including the profile of calcium-coupled GPCRs and the expression of TRP channels and STIM/Orai proteins, of further interest to investigate disturbed calcium dynamics in ADPKD.
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DuBreuil, Daniel M., Xiaofan Lai, Kevin Zhu, Grace Chahyadinata, Caroline Perner, Brenda Chiang, Ashley Battenberg, Caroline Sokol, and Brian Wainger. "Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic." Molecular Pain, December 16, 2022, 174480692211483. http://dx.doi.org/10.1177/17448069221148351.
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Sensory neuron hyperexcitability is a critical driver of pathological pain and can result from axon damage, inflammation, or neuronal stress. G-protein coupled receptor (GPCR) signaling can induce pain amplification by modulating the activation of Trp-family ionotropic receptors and voltage-gated ion channels. Here, we sought to use calcium imaging to identify novel inhibitors of the intracellular pathways that mediate sensory neuron sensitization and lead to hyperexcitability. We identified a novel stimulus cocktail consisting of L-054,264, a SST2R agonist, and CYM5541, a S1PR3 agonist, that elicits calcium responses in mouse primary sensory neurons in vitro as well as pain and thermal hypersensitivity in mice in vivo. We screened a library of 906 bioactive compounds and identified 24 hits that reduced calcium flux elicited by L-054,264/CYM5541. Among these hits, silymarin, a natural product derived from milk thistle, strongly reduced activation by the stimulation cocktail, as well as by a distinct inflammatory cocktail containing bradykinin and prostaglandin E2. Silymarin had no effect on sensory neuron excitability at baseline, but reduced calcium flux via Orai channels and downstream mediators of phospholipase C signaling. In vivo, silymarin pretreatment blocked development of adjuvant-mediated thermal hypersensitivity, indicating potential use as an anti-inflammatory analgesic.
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Blaho, Victoria, Jerold Chun, Danielle Jones, Deepa Jonnalagadda, Yasuyuki Kihara, Tony Ngo, Manisha Ray, and Valerie P. Tan. "Lysophospholipid (LPA) receptors in GtoPdb v.2021.2." IUPHAR/BPS Guide to Pharmacology CITE 2021, no. 2 (June 25, 2021). http://dx.doi.org/10.2218/gtopdb/f36/2021.2.
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Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [55, 19, 82, 129]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [40], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA2,3,4,5,6) have since been identified [82] and their gene nomenclature codified for human LPAR1, LPAR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and Lpar1, Lpar2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The crystal structure of LPA1 is solved and indicates that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [13]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA1 of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pKd = 9) [83, 104]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [128]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGFα "shedding* assay [48]. LPA LPA has been proposed to be a ligand for GPCR35 [94], supported by a recent study revealing that LPA modulates macrophage function through GPR35 [54]. However chemokine (C-X-C motif) ligand 17 (CXCL17) is reported to be a ligand for GPR35/CXCR8 [76]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [87] and TRPA1 [58]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.
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Blaho, Victoria, Jerold Chun, Danielle Jones, Deepa Jonnalagadda, Yasuyuki Kihara, Tony Ngo, Manisha Ray, and Valerie P. Tan. "Lysophospholipid (LPA) receptors in GtoPdb v.2021.3." IUPHAR/BPS Guide to Pharmacology CITE 2021, no. 3 (September 2, 2021). http://dx.doi.org/10.2218/gtopdb/f36/2021.3.
Full textAbstract:
Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [55, 19, 82, 129]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [40], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA2,3,4,5,6) have since been identified [82] and their gene nomenclature codified for human LPAR1, LPAR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and Lpar1, Lpar2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The crystal structure of LPA1 is solved and indicates that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [13]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA1 of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pKd = 9) [83, 104]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [128]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGFα "shedding* assay [48]. LPA has been proposed to be a ligand for GPR35 [94], supported by a study revealing that LPA modulates macrophage function through GPR35 [54]. However chemokine (C-X-C motif) ligand 17 (CXCL17) is reported to be a ligand for GPR35/CXCR8 [76]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [87] and TRPA1 [58]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.