scholarly journals Lysophospholipid (LPA) receptors in GtoPdb v.2021.2

2021 ◽  
Vol 2021 (2) ◽  
Author(s):  
Victoria Blaho ◽  
Jerold Chun ◽  
Danielle Jones ◽  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Ventricular Zone ◽  
Receptor Potential ◽  
Mouse Genome Informatics ◽  
Binding Pocket ◽  
Gene Nomenclature ◽  
Lpa Receptors ◽  
Sphingosine 1 Phosphate ◽  
Bona Fide ◽  
Transient Receptor

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.

scholarly journals Lysophospholipid (LPA) receptors in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Victoria Blaho ◽  
Jerold Chun ◽  
Danielle Jones ◽  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Ventricular Zone ◽  
Receptor Potential ◽  
Mouse Genome Informatics ◽  
Binding Pocket ◽  
Gene Nomenclature ◽  
Lpa Receptors ◽  
Sphingosine 1 Phosphate ◽  
Bona Fide ◽  
Transient Receptor

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.

scholarly journals Lysophospholipid (LPA) receptors (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

2020 ◽  
Vol 2020 (5) ◽  
Author(s):  
Victoria Blaho ◽  
Jerold Chun ◽  
Danielle Jones ◽  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Ventricular Zone ◽  
Receptor Potential ◽  
Binding Pocket ◽  
Binding Affinities ◽  
Lpa Receptor ◽  
Lpa Receptors ◽  
Sphingosine 1 Phosphate ◽  
Bona Fide ◽  
Transient Receptor

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.

scholarly journals Lysophospholipid (LPA) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Victoria Blaho ◽  
Jerold Chun ◽  
Aaron Frantz ◽  
Timothy Hla ◽  
Danielle Jones ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Ventricular Zone ◽  
Receptor Potential ◽  
Binding Pocket ◽  
Binding Affinities ◽  
Lpa Receptor ◽  
Lpa Receptors ◽  
Sphingosine 1 Phosphate ◽  
Bona Fide ◽  
Transient Receptor

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.

scholarly journals Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors

2011 ◽  
Vol 192 (4) ◽  
pp. 557-567 ◽  
Author(s):  
Ikuko Yonamine ◽  
Takeshi Bamba ◽  
Niraj K. Nirala ◽  
Nahid Jesmin ◽  
Teresa Kosakowska-Cholody ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Endosomal Trafficking ◽  
Loss Of Function ◽  
Late Endosomes ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Transient Receptor ◽  
G Protein Coupled

Internalized membrane proteins are either transported to late endosomes and lysosomes for degradation or recycled to the plasma membrane. Although proteins involved in trafficking and sorting have been well studied, far less is known about the lipid molecules that regulate the intracellular trafficking of membrane proteins. We studied the function of sphingosine kinases and their metabolites in endosomal trafficking using Drosophila melanogaster photoreceptors as a model system. Gain- and loss-of-function analyses show that sphingosine kinases affect trafficking of the G protein–coupled receptor Rhodopsin and the light-sensitive transient receptor potential (TRP) channel by modulating the levels of dihydrosphingosine 1 phosphate (DHS1P) and sphingosine 1 phosphate (S1P). An increase in DHS1P levels relative to S1P leads to the enhanced lysosomal degradation of Rhodopsin and TRP and retinal degeneration in wild-type photoreceptors. Our results suggest that sphingosine kinases and their metabolites modulate photoreceptor homeostasis by influencing endolysosomal trafficking of Rhodopsin and TRP.

scholarly journals Structural insights into TRPM8 inhibition and desensitization

Science ◽  
2019 ◽  
Vol 365 (6460) ◽  
pp. 1434-1440 ◽  
Author(s):  
Melinda M. Diver ◽  
Yifan Cheng ◽  
David Julius
Keyword(s):  
Conformational Changes ◽  
Calcium Binding ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Binding Pocket ◽  
Chemical Structures ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Large Rearrangements

The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo–electron microscopy structures of TRPM8 in ligand-free, antagonist-bound, or calcium-bound forms, revealing how robust conformational changes give rise to two nonconducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and we delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.

scholarly journals Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2

2017 ◽  
Vol 149 (2) ◽  
pp. 219-235 ◽  
Author(s):  
Peilin Yu ◽  
Xiwen Xue ◽  
Jianmin Zhang ◽  
Xupang Hu ◽  
Yan Wu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Structural Model ◽  
Receptor Potential ◽  
Adenosine Diphosphate ◽  
Binding Pocket ◽  
Dynamics Simulation ◽  
Structure Based Drug Design ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channel ◽  
Transient Receptor

Activation of the transient receptor potential melastatin 2 (TRPM2) channel occurs during the response to oxidative stress under physiological conditions as well as in pathological processes such as ischemia and diabetes. Accumulating evidence indicates that adenosine diphosphate ribose (ADPR) is the most important endogenous ligand of TRPM2. However, although it is known that ADPR binds to the NUDT9 homology (NUDT9-H) domain in the intracellular C-terminal region, the molecular mechanism underlying ADPR binding and activation of TRPM2 remains unknown. In this study, we generate a structural model of the NUDT9-H domain and identify the binding pocket for ADPR using induced docking and molecular dynamics simulation. We find a subset of 11 residues—H1346, T1347, T1349, L1379, G1389, S1391, E1409, D1431, R1433, L1484, and H1488—that are most likely to directly interact with ADPR. Results from mutagenesis and electrophysiology approaches support the predicted binding mechanism, indicating that ADPR binds tightly to the NUDT9-H domain, and suggest that the most significant interactions are the van der Waals forces with S1391 and L1484, polar solvation interaction with E1409, and electronic interactions (including π–π interactions) with H1346, T1347, Y1349, D1431, and H1488. These findings not only clarify the roles of a range of newly identified residues involved in ADPR binding in the TRPM2 channel, but also reveal the binding pocket for ADPR in the NUDT9-H domain, which should facilitate structure-based drug design for the TRPM2 channel.

Bipolar phospholipid sensing by TRPC5 calcium channel

2007 ◽  
Vol 35 (1) ◽  
pp. 101-104 ◽  
Author(s):  
D.J. Beech
Keyword(s):  
Plasma Membrane ◽  
Calcium Channel ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mechanisms Of Action ◽  
Permeable Channel ◽  
Sphingosine 1 Phosphate ◽  
Mammalian Homologue ◽  
Transient Receptor ◽  
Underlying Mechanisms

TRPC5 [TRP (transient receptor potential) canonical (or classical) 5] is a widely expressed mammalian homologue of Drosophila TRP, forming a calcium- and sodium-permeable channel in the plasma membrane either as a homomultimer or heteromultimer with other proteins (e.g. TRPC1). Although several factors are known to stimulate the channel, understanding of its endogenous activators and functions is limited. This paper provides a brief and focused review of our latest findings that show that TRPC5 is a sensor of important signalling phospholipids, including lysophosphatidylcholine and sphingosine 1-phosphate, acting extracellularly or intracellularly. Underlying mechanisms of action and biological relevance are discussed.

scholarly journals Sphingosine-1-Phosphate Elicits Receptor-Dependent Calcium Signaling in Retinal Amacrine Cells

2009 ◽  
Vol 102 (6) ◽  
pp. 3295-3309 ◽  
Author(s):  
Scott Crousillac ◽  
Jeremy Colonna ◽  
Emily McMains ◽  
Jill Sayes Dewey ◽  
Evanna Gleason
Keyword(s):  
Transient Receptor Potential ◽  
Pcr Amplification ◽  
Receptor Potential ◽  
Cell Voltage ◽  
Amacrine Cells ◽  
Trpc Channels ◽  
Downstream Effects ◽  
Sphingosine 1 Phosphate ◽  
Pcr Products ◽  
Transient Receptor

Evidence is emerging indicating that sphingosine-1-phosphate (S1P) participates in signaling in the retina. To determine whether S1P might be involved in signaling in the inner retina specifically, we examine the effects of this sphingolipid on cultured retinal amacrine cells. Whole cell voltage-clamp recordings reveal that S1P activates a cation current that is dependent on signaling through Gi and phospholipase C. These observations are consistent with the involvement of members of the S1P receptor family of G-protein-coupled receptors in the production of the current. Immunocytochemistry and PCR amplification provide evidence for the expression of S1P1R and S1P3R in amacrine cells. The receptor-mediated channel activity is shown to be highly sensitive to blockade by lanthanides consistent with the behavior of transient receptor potential canonical (TRPC) channels. PCR products amplified from amacrine cells reveal that TRPCs 1 and 3–7 channel subunits have the potential to be expressed. Because TRPC channels provide a Ca2+ entry pathway, we asked whether S1P caused cytosolic Ca2+ elevations in amacrine cells. We show that S1P-dependent Ca2+ elevations do occur in these cells and that they might be mediated by S1P1R and S1P3R. The Ca2+ elevations are partially due to release from internal stores, but the largest contribution is from influx across the plasma membrane. The effect of inhibition of sphingosine kinase suggests that the production of cytosolic S1P underlies the sustained nature of the Ca2+ elevations. Elucidation of the downstream effects of these signals will provide clues to the role of S1P in regulating inner retinal function.

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