α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal
Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepi...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Ichtchenko, Konstantin [verfasserIn] Khvotchev, Mikhail [verfasserIn] Kiyatkin, Nikita [verfasserIn] Simpson, Lance [verfasserIn] Sugita, Shuzo [verfasserIn] Südhof, Thomas C. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
1998 |
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| Schlagwörter: |
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| Anmerkung: |
© European Molecular Biology Organization 1998 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 17(1998), 21 vom: 02. Nov., Seite 6188-6199 |
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| Übergeordnetes Werk: |
volume:17 ; year:1998 ; number:21 ; day:02 ; month:11 ; pages:6188-6199 |
| Links: |
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| DOI / URN: |
10.1093/emboj/17.21.6188 |
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| Katalog-ID: |
SPR05780737X |
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| 024 | 7 | |a 10.1093/emboj/17.21.6188 |2 doi | |
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| 100 | 1 | |a Ichtchenko, Konstantin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal |
| 264 | 1 | |c 1998 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a © European Molecular Biology Organization 1998 | ||
| 520 | |a Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. | ||
| 650 | 4 | |a α‐latrotoxin |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a CIRL |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a latrophilin |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a neurexins |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a neurotransmitter release |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Khvotchev, Mikhail |e verfasserin |4 aut | |
| 700 | 1 | |a Kiyatkin, Nikita |e verfasserin |4 aut | |
| 700 | 1 | |a Simpson, Lance |e verfasserin |4 aut | |
| 700 | 1 | |a Sugita, Shuzo |e verfasserin |4 aut | |
| 700 | 1 | |a Südhof, Thomas C. |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:17 |g year:1998 |g number:21 |g day:02 |g month:11 |g pages:6188-6199 |
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| 952 | |d 17 |j 1998 |e 21 |b 02 |c 11 |h 6188-6199 | ||
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1998 |
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1998 |
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10.1093/emboj/17.21.6188 doi (DE-627)SPR05780737X (SPR)17.21.6188-e DE-627 ger DE-627 rakwb eng Ichtchenko, Konstantin verfasserin aut α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal 1998 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1998 Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. α‐latrotoxin (dpeaa)DE-He213 CIRL (dpeaa)DE-He213 latrophilin (dpeaa)DE-He213 neurexins (dpeaa)DE-He213 neurotransmitter release (dpeaa)DE-He213 Khvotchev, Mikhail verfasserin aut Kiyatkin, Nikita verfasserin aut Simpson, Lance verfasserin aut Sugita, Shuzo verfasserin aut Südhof, Thomas C. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 17(1998), 21 vom: 02. Nov., Seite 6188-6199 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:17 year:1998 number:21 day:02 month:11 pages:6188-6199 https://dx.doi.org/10.1093/emboj/17.21.6188 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 17 1998 21 02 11 6188-6199 |
| spelling |
10.1093/emboj/17.21.6188 doi (DE-627)SPR05780737X (SPR)17.21.6188-e DE-627 ger DE-627 rakwb eng Ichtchenko, Konstantin verfasserin aut α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal 1998 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1998 Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. α‐latrotoxin (dpeaa)DE-He213 CIRL (dpeaa)DE-He213 latrophilin (dpeaa)DE-He213 neurexins (dpeaa)DE-He213 neurotransmitter release (dpeaa)DE-He213 Khvotchev, Mikhail verfasserin aut Kiyatkin, Nikita verfasserin aut Simpson, Lance verfasserin aut Sugita, Shuzo verfasserin aut Südhof, Thomas C. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 17(1998), 21 vom: 02. Nov., Seite 6188-6199 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:17 year:1998 number:21 day:02 month:11 pages:6188-6199 https://dx.doi.org/10.1093/emboj/17.21.6188 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 17 1998 21 02 11 6188-6199 |
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10.1093/emboj/17.21.6188 doi (DE-627)SPR05780737X (SPR)17.21.6188-e DE-627 ger DE-627 rakwb eng Ichtchenko, Konstantin verfasserin aut α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal 1998 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1998 Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. α‐latrotoxin (dpeaa)DE-He213 CIRL (dpeaa)DE-He213 latrophilin (dpeaa)DE-He213 neurexins (dpeaa)DE-He213 neurotransmitter release (dpeaa)DE-He213 Khvotchev, Mikhail verfasserin aut Kiyatkin, Nikita verfasserin aut Simpson, Lance verfasserin aut Sugita, Shuzo verfasserin aut Südhof, Thomas C. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 17(1998), 21 vom: 02. Nov., Seite 6188-6199 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:17 year:1998 number:21 day:02 month:11 pages:6188-6199 https://dx.doi.org/10.1093/emboj/17.21.6188 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 17 1998 21 02 11 6188-6199 |
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10.1093/emboj/17.21.6188 doi (DE-627)SPR05780737X (SPR)17.21.6188-e DE-627 ger DE-627 rakwb eng Ichtchenko, Konstantin verfasserin aut α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal 1998 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1998 Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. α‐latrotoxin (dpeaa)DE-He213 CIRL (dpeaa)DE-He213 latrophilin (dpeaa)DE-He213 neurexins (dpeaa)DE-He213 neurotransmitter release (dpeaa)DE-He213 Khvotchev, Mikhail verfasserin aut Kiyatkin, Nikita verfasserin aut Simpson, Lance verfasserin aut Sugita, Shuzo verfasserin aut Südhof, Thomas C. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 17(1998), 21 vom: 02. Nov., Seite 6188-6199 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:17 year:1998 number:21 day:02 month:11 pages:6188-6199 https://dx.doi.org/10.1093/emboj/17.21.6188 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 17 1998 21 02 11 6188-6199 |
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10.1093/emboj/17.21.6188 doi (DE-627)SPR05780737X (SPR)17.21.6188-e DE-627 ger DE-627 rakwb eng Ichtchenko, Konstantin verfasserin aut α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal 1998 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1998 Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. α‐latrotoxin (dpeaa)DE-He213 CIRL (dpeaa)DE-He213 latrophilin (dpeaa)DE-He213 neurexins (dpeaa)DE-He213 neurotransmitter release (dpeaa)DE-He213 Khvotchev, Mikhail verfasserin aut Kiyatkin, Nikita verfasserin aut Simpson, Lance verfasserin aut Sugita, Shuzo verfasserin aut Südhof, Thomas C. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 17(1998), 21 vom: 02. Nov., Seite 6188-6199 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:17 year:1998 number:21 day:02 month:11 pages:6188-6199 https://dx.doi.org/10.1093/emboj/17.21.6188 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 17 1998 21 02 11 6188-6199 |
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Enthalten in The EMBO Journal 17(1998), 21 vom: 02. Nov., Seite 6188-6199 volume:17 year:1998 number:21 day:02 month:11 pages:6188-6199 |
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Enthalten in The EMBO Journal 17(1998), 21 vom: 02. Nov., Seite 6188-6199 volume:17 year:1998 number:21 day:02 month:11 pages:6188-6199 |
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α‐latrotoxin CIRL latrophilin neurexins neurotransmitter release |
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Ichtchenko, Konstantin @@aut@@ Khvotchev, Mikhail @@aut@@ Kiyatkin, Nikita @@aut@@ Simpson, Lance @@aut@@ Sugita, Shuzo @@aut@@ Südhof, Thomas C. @@aut@@ |
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1998-11-02T00:00:00Z |
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We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. 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|
| author |
Ichtchenko, Konstantin |
| spellingShingle |
Ichtchenko, Konstantin misc α‐latrotoxin misc CIRL misc latrophilin misc neurexins misc neurotransmitter release α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal |
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α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal α‐latrotoxin (dpeaa)DE-He213 CIRL (dpeaa)DE-He213 latrophilin (dpeaa)DE-He213 neurexins (dpeaa)DE-He213 neurotransmitter release (dpeaa)DE-He213 |
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misc α‐latrotoxin misc CIRL misc latrophilin misc neurexins misc neurotransmitter release |
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α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal |
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α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal |
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Ichtchenko, Konstantin Khvotchev, Mikhail Kiyatkin, Nikita Simpson, Lance Sugita, Shuzo Südhof, Thomas C. |
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α‐latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal |
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α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal |
| abstract |
Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. © European Molecular Biology Organization 1998 |
| abstractGer |
Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. © European Molecular Biology Organization 1998 |
| abstract_unstemmed |
Abstract α‐Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Iα. We have now produced recombinant α‐latrotoxin ($ Ltx^{WT} $) that is as active as native α‐latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three α‐latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four‐residue insertion. All four α‐latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant $ Ltx^{N4C} $ exhibited receptor‐binding affinities identical to wild‐type $ Ltx^{WT} $, bound to CL1 and neurexin Iα as well as $ Ltx^{WT} $, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by α‐latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with $ La^{3+} $ and $ Cd^{2+} $. $ La^{3+} $ blocked release triggered by $ Ltx^{WT} $, whereas $ Cd^{2+} $ enhanced it. Both cations, however, had no effect on the stimulation by $ Ltx^{WT} $ of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by α‐latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit α‐latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor‐independent activity of α‐latrotoxin that is selectively inhibited by the $ Ltx^{N4C} $ mutation and by $ La^{3+} $. © European Molecular Biology Organization 1998 |
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21 |
| title_short |
α‐Latrotoxin action probed with recombinant toxin: receptors recruit α‐latrotoxin but do not transduce an exocytotic signal |
| url |
https://dx.doi.org/10.1093/emboj/17.21.6188 |
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| author2 |
Khvotchev, Mikhail Kiyatkin, Nikita Simpson, Lance Sugita, Shuzo Südhof, Thomas C. |
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Khvotchev, Mikhail Kiyatkin, Nikita Simpson, Lance Sugita, Shuzo Südhof, Thomas C. |
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| doi_str |
10.1093/emboj/17.21.6188 |
| up_date |
2024-10-16T04:50:49.968Z |
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|
| score |
7.40189 |