Apamin structure and pharmacology revisited
Apamin is often cited as one of the few substances selectively acting on small-conductance Ca2+-activated potassium channels (KCa2). However, published pharmacological and structural data remain controversial. Here, we investigated the molecular pharmacology of apamin by two-electrode voltage-clamp...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.977440/full |
| _version_ | 1811183580672425984 |
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| author | Alexey I. Kuzmenkov Steve Peigneur Joshua A. Nasburg Konstantin S. Mineev Konstantin S. Mineev Maxim V. Nikolaev Ernesto Lopes Pinheiro-Junior Alexander S. Arseniev Alexander S. Arseniev Heike Wulff Jan Tytgat Alexander A. Vassilevski Alexander A. Vassilevski |
| author_facet | Alexey I. Kuzmenkov Steve Peigneur Joshua A. Nasburg Konstantin S. Mineev Konstantin S. Mineev Maxim V. Nikolaev Ernesto Lopes Pinheiro-Junior Alexander S. Arseniev Alexander S. Arseniev Heike Wulff Jan Tytgat Alexander A. Vassilevski Alexander A. Vassilevski |
| author_sort | Alexey I. Kuzmenkov |
| collection | DOAJ |
| description | Apamin is often cited as one of the few substances selectively acting on small-conductance Ca2+-activated potassium channels (KCa2). However, published pharmacological and structural data remain controversial. Here, we investigated the molecular pharmacology of apamin by two-electrode voltage-clamp in Xenopus laevis oocytes and patch-clamp in HEK293, COS7, and CHO cells expressing the studied ion channels, as well as in isolated rat brain neurons. The microtitre broth dilution method was used for antimicrobial activity screening. The spatial structure of apamin in aqueous solution was determined by NMR spectroscopy. We tested apamin against 42 ion channels (KCa, KV, NaV, nAChR, ASIC, and others) and confirmed its unique selectivity to KCa2 channels. No antimicrobial activity was detected for apamin against Gram-positive or Gram-negative bacteria. The NMR solution structure of apamin was deposited in the Protein Data Bank. The results presented here demonstrate that apamin is a selective nanomolar or even subnanomolar-affinity KCa2 inhibitor with no significant effects on other molecular targets. The spatial structure as well as ample functional data provided here support the use of apamin as a KCa2-selective pharmacological tool and as a template for drug design. |
| first_indexed | 2024-04-11T09:48:09Z |
| format | Article |
| id | doaj.art-03250e942dc5484ca71aad07a5e99041 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T09:48:09Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-03250e942dc5484ca71aad07a5e990412022-12-22T04:30:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.977440977440Apamin structure and pharmacology revisitedAlexey I. Kuzmenkov0Steve Peigneur1Joshua A. Nasburg2Konstantin S. Mineev3Konstantin S. Mineev4Maxim V. Nikolaev5Ernesto Lopes Pinheiro-Junior6Alexander S. Arseniev7Alexander S. Arseniev8Heike Wulff9Jan Tytgat10Alexander A. Vassilevski11Alexander A. Vassilevski12Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaToxicology and Pharmacology, KU Leuven, Leuven, BelgiumDepartment of Pharmacology, University of California, Davis, Davis, CA, United StatesShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaMoscow Institute of Physics and Technology, Moscow Region, Dolgoprudny, RussiaSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Saint Petersburg, RussiaToxicology and Pharmacology, KU Leuven, Leuven, BelgiumShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaMoscow Institute of Physics and Technology, Moscow Region, Dolgoprudny, RussiaDepartment of Pharmacology, University of California, Davis, Davis, CA, United StatesToxicology and Pharmacology, KU Leuven, Leuven, BelgiumShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaMoscow Institute of Physics and Technology, Moscow Region, Dolgoprudny, RussiaApamin is often cited as one of the few substances selectively acting on small-conductance Ca2+-activated potassium channels (KCa2). However, published pharmacological and structural data remain controversial. Here, we investigated the molecular pharmacology of apamin by two-electrode voltage-clamp in Xenopus laevis oocytes and patch-clamp in HEK293, COS7, and CHO cells expressing the studied ion channels, as well as in isolated rat brain neurons. The microtitre broth dilution method was used for antimicrobial activity screening. The spatial structure of apamin in aqueous solution was determined by NMR spectroscopy. We tested apamin against 42 ion channels (KCa, KV, NaV, nAChR, ASIC, and others) and confirmed its unique selectivity to KCa2 channels. No antimicrobial activity was detected for apamin against Gram-positive or Gram-negative bacteria. The NMR solution structure of apamin was deposited in the Protein Data Bank. The results presented here demonstrate that apamin is a selective nanomolar or even subnanomolar-affinity KCa2 inhibitor with no significant effects on other molecular targets. The spatial structure as well as ample functional data provided here support the use of apamin as a KCa2-selective pharmacological tool and as a template for drug design.https://www.frontiersin.org/articles/10.3389/fphar.2022.977440/fullapaminApis melliferabee venomcalcium-activated potassium channelion channelspatial structure |
| spellingShingle | Alexey I. Kuzmenkov Steve Peigneur Joshua A. Nasburg Konstantin S. Mineev Konstantin S. Mineev Maxim V. Nikolaev Ernesto Lopes Pinheiro-Junior Alexander S. Arseniev Alexander S. Arseniev Heike Wulff Jan Tytgat Alexander A. Vassilevski Alexander A. Vassilevski Apamin structure and pharmacology revisited Frontiers in Pharmacology apamin Apis mellifera bee venom calcium-activated potassium channel ion channel spatial structure |
| title | Apamin structure and pharmacology revisited |
| title_full | Apamin structure and pharmacology revisited |
| title_fullStr | Apamin structure and pharmacology revisited |
| title_full_unstemmed | Apamin structure and pharmacology revisited |
| title_short | Apamin structure and pharmacology revisited |
| title_sort | apamin structure and pharmacology revisited |
| topic | apamin Apis mellifera bee venom calcium-activated potassium channel ion channel spatial structure |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.977440/full |
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