11 results on '"NAADP"'
Search Results
2. Electrophysiology of Endolysosomal Two-Pore Channels: A Current Account
- Author
-
Sandip Patel, Yu Yuan, Cheng-Chang Chen, Dawid Jaślan, Gihan Gunaratne, Christian Grimm, Taufiq Rahman, and Jonathan S. Marchant
- Subjects
TPC1 ,TPC2 ,TPCN1 ,TPCN2 ,NAADP ,PI(3,5)P2 ,Cytology ,QH573-671 - Abstract
Two-pore channels TPC1 and TPC2 are ubiquitously expressed pathophysiologically relevant proteins that reside on endolysosomal vesicles. Here, we review the electrophysiology of these channels. Direct macroscopic recordings of recombinant TPCs expressed in enlarged lysosomes in mammalian cells or vacuoles in plants and yeast demonstrate gating by the Ca2+-mobilizing messenger NAADP and/or the lipid PI(3,5)P2. TPC currents are regulated by H+, Ca2+, and Mg2+ (luminal and/or cytosolic), as well as protein kinases, and they are impacted by single-nucleotide polymorphisms linked to pigmentation. Bisbenzylisoquinoline alkaloids, flavonoids, and several approved drugs demonstrably block channel activity. Endogenous TPC currents have been recorded from a number of primary cell types and cell lines. Many of the properties of endolysosomal TPCs are recapitulated upon rerouting channels to the cell surface, allowing more facile recording through conventional electrophysiological means. Single-channel analyses have provided high-resolution insight into both monovalent and divalent permeability. The discovery of small-molecule activators of TPC2 that toggle the ion selectivity from a Ca2+-permeable (NAADP-like) state to a Na+-selective (PI(3,5)P2-like) state explains discrepancies in the literature relating to the permeability of TPCs. Identification of binding proteins that confer NAADP-sensitive currents confirm that indirect, remote gating likely underpins the inconsistent observations of channel activation by NAADP.
- Published
- 2022
- Full Text
- View/download PDF
3. NAADP Signaling: New Kids on the Block
- Author
-
Andreas H. Guse
- Subjects
NAADP ,Ca2+ signaling ,Ca2+ microdomains ,dual NADPH oxidase (DUOX) ,hematological and neurological expressed 1-like protein (HN1L)/Jupiter microtubule-associated homolog 2 (JPT2) ,ryanodine receptor (RYR) ,Cytology ,QH573-671 - Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a universal Ca2+ mobilizing second messenger essential for initiation of Ca2+ signaling. Recently, novel molecular mechanisms of both its rapid formation upon receptor stimulation and its mode of action were discovered. Dual NADPH oxidase 2 (DUOX2) and hematological and neurological expressed 1-like protein (HN1L)/Jupiter microtubule-associated homolog 2 (JPT2) were discovered as NAADP-forming enzyme and NAADP receptor/binding protein—the new kids on the block. These novel aspects are reviewed and integrated into the previous view of NAADP signaling.
- Published
- 2022
- Full Text
- View/download PDF
4. Trans-Ned 19-Mediated Antagonism of Nicotinic Acid Adenine Nucleotide—Mediated Calcium Signaling Regulates Th17 Cell Plasticity in Mice
- Author
-
Mikołaj Nawrocki, Niels Lory, Tanja Bedke, Friederike Stumme, Björn-Phillip Diercks, Andreas H. Guse, Chris Meier, Nicola Gagliani, Hans-Willi Mittrücker, and Samuel Huber
- Subjects
adenine nucleotides ,NAADP ,Ca2+ signaling ,T cells ,immune regulation ,inflammatory diseases ,Cytology ,QH573-671 - Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing agent and its inhibition proved to inhibit T-cell activation. However, the impact of the NAADP signaling on CD4+ T-cell differentiation and plasticity and on the inflammation in tissues other than the central nervous system remains unclear. In this study, we used an antagonist of NAADP signaling, trans-Ned 19, to study the role of NAADP in CD4+ T-cell differentiation and effector function. Partial blockade of NAADP signaling in naïve CD4+ T cells in vitro promoted the differentiation of Th17 cells. Interestingly, trans-Ned 19 also promoted the production of IL-10, co-expression of LAG-3 and CD49b and increased the suppressive capacity of Th17 cells. Moreover, using an IL-17A fate mapping mouse model, we showed that NAADP inhibition promotes conversion of Th17 cells into regulatory T cells in vitro and in vivo. In line with the results, we found that inhibiting NAADP ameliorates disease in a mouse model of intestinal inflammation. Thus, these results reveal a novel function of NAADP in controlling the differentiation and plasticity of CD4+ T cells.
- Published
- 2021
- Full Text
- View/download PDF
5. The Role of Two-Pore Channels in Norepinephrine-Induced [Ca2+]i Rise in Rat Aortic Smooth Muscle Cells and Aorta Contraction
- Author
-
Sergei K. Trufanov, Elena Yu. Rybakova, Piotr P. Avdonin, Alexandra A. Tsitrina, Irina L. Zharkikh, Nikolay V. Goncharov, Richard O. Jenkins, and Pavel V. Avdonin
- Subjects
norepinephrine ,calcium ,two-pore channels ,smooth muscle cells ,ned 19 ,naadp ,sirna ,aorta ,Cytology ,QH573-671 - Abstract
Second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) triggers Ca2+ release via two-pore channels (TPCs) localized in endolysosomal vesicles. The aim of the present work is to evaluate the role of TPCs in the action of norepinephrine (NE), angiotensin II (AngII), vasopressin (AVP), and 5-hydroxytriptamine (5-HT) on free cytoplasmic calcium concentration ([Ca2+]i) in smooth muscle cells (SMCs) isolated from rat aorta and on aorta contraction. To address this issue, the NAADP structural analogue and inhibitor of TPCs, NED 19, was applied. We have demonstrated a high degree of colocalization of the fluorescent signals of cis-NED 19 and endolysosmal probe LysoTracker in SMCs. Both cis- or trans-NED 19 inhibited the rise of [Ca2+]i in SMCs induced by 100 μM NE by 50−60%. IC50 for cis- and trans-NED 19 were 2.7 and 8.9 μM, respectively. The inhibition by NED 19 stereoisomers of the effects of AngII, AVP, and 5-HT was much weaker. Both forms of NED 19 caused relaxation of aortic rings preconstricted by NE, with relative potency of cis-NED 19 several times higher than that of trans-NED 19. Inhibition by cis-NED 19 of NE-induced contraction was maintained after intensive washing and slowly reversed within an hour of incubation. Cis- and trans-NED 19 did not cause decrease in the force of aorta contraction in response to Ang II and AVP, and only slightly relaxed aorta preconstricted by 5-HT and by KCl. Suppression of TPC1 in SMCs with siRNA caused a 40% decrease in [Ca2+]i in response to NE, whereas siRNA against TPC2 did not change NE calcium signaling. These data suggest that TPC1 is involved in the NE-stimulated [Ca2+]i rise in SMCs. Inhibition of TPC1 activity by NED 19 could be the reason for partial inhibition of aortic rings contraction in response to NE.
- Published
- 2019
- Full Text
- View/download PDF
6. Trans-Ned 19-Mediated Antagonism of Nicotinic Acid Adenine Nucleotide—Mediated Calcium Signaling Regulates Th17 Cell Plasticity in Mice
- Author
-
Friederike Stumme, Tanja Bedke, Hans-Willi Mittrücker, Chris Meier, Mikolaj Nawrocki, Samuel Huber, Niels Lory, Nicola Gagliani, Björn-Phillip Diercks, and Andreas H. Guse
- Subjects
CD3 Complex ,adenine nucleotides ,QH301-705.5 ,Cell Plasticity ,NAADP ,Receptors, Antigen, T-Cell ,T cells ,inflammatory diseases ,Mice, Transgenic ,Inflammation ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Article ,Piperazines ,CD49b ,chemistry.chemical_compound ,Adenine nucleotide ,Ca2+ signaling ,immune therapy ,medicine ,Animals ,Calcium Signaling ,Biology (General) ,Cell Proliferation ,Calcium signaling ,Nicotinic acid adenine dinucleotide phosphate ,immune regulation ,Cell Differentiation ,Forkhead Transcription Factors ,General Medicine ,Th1 Cells ,In vitro ,Interleukin-10 ,Up-Regulation ,Cell biology ,Intestines ,Mice, Inbred C57BL ,Disease Models, Animal ,Nicotinic agonist ,chemistry ,Th17 Cells ,Calcium ,medicine.symptom ,NADP ,Carbolines - Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing agent and its inhibition proved to inhibit T-cell activation. However, the impact of the NAADP signaling on CD4+ T-cell differentiation and plasticity and on the inflammation in tissues other than the central nervous system remains unclear. In this study, we used an antagonist of NAADP signaling, trans-Ned 19, to study the role of NAADP in CD4+ T-cell differentiation and effector function. Partial blockade of NAADP signaling in naïve CD4+ T cells in vitro promoted the differentiation of Th17 cells. Interestingly, trans-Ned 19 also promoted the production of IL-10, co-expression of LAG-3 and CD49b and increased the suppressive capacity of Th17 cells. Moreover, using an IL-17A fate mapping mouse model, we showed that NAADP inhibition promotes conversion of Th17 cells into regulatory T cells in vitro and in vivo. In line with the results, we found that inhibiting NAADP ameliorates disease in a mouse model of intestinal inflammation. Thus, these results reveal a novel function of NAADP in controlling the differentiation and plasticity of CD4+ T cells.
- Published
- 2021
- Full Text
- View/download PDF
7. Enzymology of Ca 2+ -Mobilizing Second Messengers Derived from NAD: From NAD Glycohydrolases to (Dual) NADPH Oxidases.
- Author
-
Guse AH
- Subjects
- Glycoside Hydrolases, Second Messenger Systems, Adenosine Diphosphate Ribose, NAD+ Nucleosidase metabolism, NAD metabolism, NADPH Oxidases
- Abstract
Nicotinamide adenine dinucleotide (NAD) and its 2'-phosphorylated cousin NADP are precursors for the enzymatic formation of the Ca
2+ -mobilizing second messengers adenosine diphosphoribose (ADPR), 2'-deoxy-ADPR, cyclic ADPR, and nicotinic acid adenine dinucleotide phosphate (NAADP). The enzymes involved are either NAD glycohydrolases CD38 or sterile alpha toll/interleukin receptor motif containing-1 (SARM1), or (dual) NADPH oxidases (NOX/DUOX). Enzymatic function(s) are reviewed and physiological role(s) in selected cell systems are discussed., Competing Interests: The author declares no conflict of interest.- Published
- 2023
- Full Text
- View/download PDF
8. Electrophysiology of Endolysosomal Two-Pore Channels: A Current Account.
- Author
-
Patel S, Yuan Y, Chen CC, Jaślan D, Gunaratne G, Grimm C, Rahman T, and Marchant JS
- Subjects
- Animals, Cytosol metabolism, Endosomes metabolism, Lysosomes metabolism, Mammals metabolism, Calcium metabolism, Calcium Channels metabolism
- Abstract
Two-pore channels TPC1 and TPC2 are ubiquitously expressed pathophysiologically relevant proteins that reside on endolysosomal vesicles. Here, we review the electrophysiology of these channels. Direct macroscopic recordings of recombinant TPCs expressed in enlarged lysosomes in mammalian cells or vacuoles in plants and yeast demonstrate gating by the Ca
2+ -mobilizing messenger NAADP and/or the lipid PI(3,5)P2 . TPC currents are regulated by H+ , Ca2+ , and Mg2+ (luminal and/or cytosolic), as well as protein kinases, and they are impacted by single-nucleotide polymorphisms linked to pigmentation. Bisbenzylisoquinoline alkaloids, flavonoids, and several approved drugs demonstrably block channel activity. Endogenous TPC currents have been recorded from a number of primary cell types and cell lines. Many of the properties of endolysosomal TPCs are recapitulated upon rerouting channels to the cell surface, allowing more facile recording through conventional electrophysiological means. Single-channel analyses have provided high-resolution insight into both monovalent and divalent permeability. The discovery of small-molecule activators of TPC2 that toggle the ion selectivity from a Ca2+ -permeable (NAADP-like) state to a Na+ -selective (PI(3,5)P2 -like) state explains discrepancies in the literature relating to the permeability of TPCs. Identification of binding proteins that confer NAADP-sensitive currents confirm that indirect, remote gating likely underpins the inconsistent observations of channel activation by NAADP.- Published
- 2022
- Full Text
- View/download PDF
9. NAADP Signaling: New Kids on the Block.
- Author
-
Guse AH
- Subjects
- Carrier Proteins metabolism, NADP analogs & derivatives, NADP metabolism, Second Messenger Systems, Calcium metabolism, Calcium Signaling
- Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a universal Ca
2+ mobilizing second messenger essential for initiation of Ca2+ signaling. Recently, novel molecular mechanisms of both its rapid formation upon receptor stimulation and its mode of action were discovered. Dual NADPH oxidase 2 (DUOX2) and hematological and neurological expressed 1-like protein (HN1L)/Jupiter microtubule-associated homolog 2 (JPT2) were discovered as NAADP-forming enzyme and NAADP receptor/binding protein-the new kids on the block. These novel aspects are reviewed and integrated into the previous view of NAADP signaling.- Published
- 2022
- Full Text
- View/download PDF
10. Trans-Ned 19-Mediated Antagonism of Nicotinic Acid Adenine Nucleotide-Mediated Calcium Signaling Regulates Th17 Cell Plasticity in Mice.
- Author
-
Nawrocki M, Lory N, Bedke T, Stumme F, Diercks BP, Guse AH, Meier C, Gagliani N, Mittrücker HW, and Huber S
- Subjects
- Animals, CD3 Complex metabolism, Calcium metabolism, Cell Differentiation drug effects, Cell Proliferation drug effects, Disease Models, Animal, Forkhead Transcription Factors metabolism, Inflammation pathology, Interleukin-10 metabolism, Intestines pathology, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Mice, Inbred C57BL, Mice, Transgenic, NADP antagonists & inhibitors, NADP metabolism, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, Th1 Cells drug effects, Th1 Cells immunology, Th17 Cells drug effects, Up-Regulation drug effects, Mice, Calcium Signaling drug effects, Carbolines pharmacology, Cell Plasticity drug effects, NADP analogs & derivatives, Piperazines pharmacology, Th17 Cells cytology, Th17 Cells immunology
- Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca
2+ mobilizing agent and its inhibition proved to inhibit T-cell activation. However, the impact of the NAADP signaling on CD4+ T-cell differentiation and plasticity and on the inflammation in tissues other than the central nervous system remains unclear. In this study, we used an antagonist of NAADP signaling, trans-Ned 19, to study the role of NAADP in CD4+ T-cell differentiation and effector function. Partial blockade of NAADP signaling in naïve CD4+ T cells in vitro promoted the differentiation of Th17 cells. Interestingly, trans-Ned 19 also promoted the production of IL-10, co-expression of LAG-3 and CD49b and increased the suppressive capacity of Th17 cells. Moreover, using an IL-17A fate mapping mouse model, we showed that NAADP inhibition promotes conversion of Th17 cells into regulatory T cells in vitro and in vivo. In line with the results, we found that inhibiting NAADP ameliorates disease in a mouse model of intestinal inflammation. Thus, these results reveal a novel function of NAADP in controlling the differentiation and plasticity of CD4+ T cells.- Published
- 2021
- Full Text
- View/download PDF
11. The Role of Two-Pore Channels in Norepinephrine-Induced [Ca 2+ ] i Rise in Rat Aortic Smooth Muscle Cells and Aorta Contraction.
- Author
-
Trufanov SK, Rybakova EY, Avdonin PP, Tsitrina AA, Zharkikh IL, Goncharov NV, Jenkins RO, and Avdonin PV
- Subjects
- Animals, Aorta drug effects, Aorta metabolism, Carbolines pharmacology, Cells, Cultured, Human Umbilical Vein Endothelial Cells, Humans, Intracellular Space drug effects, Intracellular Space metabolism, Male, Piperazines pharmacology, Rats, Rats, Wistar, Aorta cytology, Calcium metabolism, Calcium Channels physiology, Myocardial Contraction drug effects, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle metabolism, Norepinephrine pharmacology
- Abstract
Second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) triggers Ca
2+ release via two-pore channels (TPCs) localized in endolysosomal vesicles. The aim of the present work is to evaluate the role of TPCs in the action of norepinephrine (NE), angiotensin II (AngII), vasopressin (AVP), and 5-hydroxytriptamine (5-HT) on free cytoplasmic calcium concentration ([Ca2+ ]i ) in smooth muscle cells (SMCs) isolated from rat aorta and on aorta contraction. To address this issue, the NAADP structural analogue and inhibitor of TPCs, NED 19, was applied. We have demonstrated a high degree of colocalization of the fluorescent signals of cis -NED 19 and endolysosmal probe LysoTracker in SMCs. Both cis - or trans -NED 19 inhibited the rise of [Ca2+ ]i in SMCs induced by 100 μM NE by 50-60%. IC50 for cis - and trans -NED 19 were 2.7 and 8.9 μM, respectively. The inhibition by NED 19 stereoisomers of the effects of AngII, AVP, and 5-HT was much weaker. Both forms of NED 19 caused relaxation of aortic rings preconstricted by NE, with relative potency of cis -NED 19 several times higher than that of trans -NED 19. Inhibition by cis -NED 19 of NE-induced contraction was maintained after intensive washing and slowly reversed within an hour of incubation. Cis - and trans -NED 19 did not cause decrease in the force of aorta contraction in response to Ang II and AVP, and only slightly relaxed aorta preconstricted by 5-HT and by KCl. Suppression of TPC1 in SMCs with siRNA caused a 40% decrease in [Ca2+ ]i in response to NE, whereas siRNA against TPC2 did not change NE calcium signaling. These data suggest that TPC1 is involved in the NE-stimulated [Ca2+ ]i rise in SMCs. Inhibition of TPC1 activity by NED 19 could be the reason for partial inhibition of aortic rings contraction in response to NE.- Published
- 2019
- Full Text
- View/download PDF
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