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1. Characterization of the σ-Pore in Mutant hKv1.3 Potassium Channels

Author

Pavel Tyutyaev and Stephan Grissmer

Subjects
Potassium channel, Kv1.3 channel, σ-pore, Electrophysiology, Patch-clamp, Physiology, QP1-981, Biochemistry, QD415-436
Abstract

Background/Aims: The replacement of the amino acid valine at position 388 (Shaker position 438) in hKv1.3 channels or at the homologue position 370 in hKv1.2 channels resulted in a channel with two different ion conducting pathways: One pathway was the central, potassium-selective α-pore, that was sensitive to block by peptide toxins (CTX or KTX in the hKv1.3_V388C channel and CTX or MTX in the hKv1.2_V370C channel). The other pathway (σ-pore) was behind the central α-pore creating an inward current at potentials more negative than -100 mV, a potential range where the central α-pore was closed. In addition, current through the σ-pore could not be reduced by CTX, KTX or MTX in the hKv1.3_V388C or the hKv1.2_V370C channel, respectively. Methods: For a more detailed characterization of the σ-pore, we created a trimer consisting of three hKv1.3_V388C α-subunits linked together and characterized current through this trimeric hKv1.3_V388C channel. Additionally, we determined which amino acids line the σ-pore in the tetrameric hKv1.3_V388C channel by replacing single amino acids in the tetrameric hKv1.3_V388C mutant channel that could be involved in σ-pore formation. Results: Overexpression of the trimeric hKv1.3_V388C channel in COS-7 cells yielded typical σ-pore currents at potentials more negative than -100 mV similar to what was observed for the tetrameric hKv1.3_V388C channel. Electrophysiological properties of the trimeric and tetrameric channel were similar: currents could be observed at potentials more negative than -100 mV, were not carried by protons or chloride ions, and could not be reduced by peptide toxins (CTX, MTX) or TEA. The σ-pore was mostly permeable to Na+ and Li+. In addition, in our site-directed mutagenesis experiments, we created a number of new double mutant channels in the tetrameric hKv1.3_V388C background channel. Two of these tetrameric double mutant channels (hKv1.3_V388C_T392Y and hKv1.3_V388C_Y395W) did not show currents through the σ-pore. Conclusions: From our experiments with the trimeric hKv1.3_V388C channel we conclude that the σ-pore exists in hKv1.3_V388C channels independently of the α-pore. From our site-directed mutagenesis experiments in the tetrameric hKv1.3_V388C channel we conclude that amino acid position 392 and 395 (Shaker position 442 and 445) line the σ-pore.

Published
2018
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2. Kinetic Aspects of Verapamil Binding (On-Rate) on Wild-Type and Six hKv1.3 Mutant Channels

Author

Ann-Kathrin Diesch and Stephan Grissmer

Subjects
Potassium channel, Kv1.3 channel, Patch-clamp, Verapamil, Open channel block, Electrophysiology, Physiology, QP1-981, Biochemistry, QD415-436
Abstract

Background/Aims: The human-voltage gated Kv1.3 channel (hKv1.3) is expressed in T- and B lymphocytes. Verapamil is able to block hKv1.3 channels. We characterized the effect of verapamil on currents through hKv1.3 channels paying special attention to the on-rate (kon) of verapamil. By comparing on-rates obtained in wild-type (wt) and mutant channels a binding pocket for verapamil and impacts of different amino acid residues should be investigated. Methods: Using the whole-cell patch clamp technique the action of verapamil on currents through wild-type and six hKv1.3 mutant channels in the open state was investigated by measuring the time course of the open channel block in order to calculate kon of verapamil. Results: The on-rate of verapamil to block current through hKv1.3_T419C mutant channels is similar to that obtained for hKv1.3_wt channels whereas the on-rate of verapamil to block currents through hKv1.3_L417C and hKv1.3_L418C mutant channels was ∼ 3 times slower compared to in wt channels. The on-rate of verapamil to block currents through hKv1.3_L346C and the double mutant hKv1.3_L346C_L418C channel was ∼ 2 times slower compared to that obtained in the wt channel. The hKv1.3_I420C mutant channel reduced the on-rate of verapamil to block currents ∼ 6 fold. Conclusions: We conclude that position 420 in hKv1.3 channels maximally interferes with verapamil reaching its binding site to block the channel. Positions 417 and 418 in hKv1.3 channels partially hinder verapamil reaching its binding site to block the channel whereas position 419 may not interfere with verapamil at all. Mutant hKv1.3_L346C and hKv1.3_L346C_L418C mutant channels might indirectly influence the ability of verapamil reaching its binding site to block current.

Published
2017
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3. Observation of σ-pore currents in mutant hKv1.2_V370C potassium channels.

Author

Pavel Tyutyaev and Stephan Grissmer

Subjects
Medicine, Science
Abstract

Current through the σ-pore was first detected in hKv1.3_V388C channels, where the V388C mutation in hKv1.3 channels opened a new pathway (σ-pore) behind the central α-pore. Typical for this mutant channel was inward current at potentials more negative than -100 mV when the central α-pore was closed. The α-pore blockers such as TEA+ and peptide toxins (CTX, MTX) could not reduce current through the σ-pore of hKv1.3_V388C channels. This new pathway would proceed in parallel to the α-pore in the S6-S6 interface gap. To see whether this phenomenon is restricted to hKv1.3 channels we mutated hKv1.2 at the homologue position (hKv1.2_V370C). By overexpression of hKv1.2_V370C mutant channels in COS-7 cells we could show typical σ-currents. The electrophysiological properties of the σ-pore in hKv1.3_V388C and hKv1.2_V370C mutant channels were similar. The σ-pore of hKv1.2_V370C channels was most permeable to Na+ and Li+ whereas Cl- and protons did not influence current through the σ-pore. Tetraethylammonium (TEA+), charybdotoxin (CTX) and maurotoxin (MTX), known α-pore blockers, could not reduce current through the σ-pore of hKv1.2_V370C channels. Taken together we conclude that the observation of σ-pore currents is not restricted to Kv1.3 potassium channels but can also be observed in a closely related potassium channel. This finding could have implications in the treatment of different ion channel diseases linked to mutations of the respective channels in regions close to homologue position investigated by us.

Published
2017
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4. Evidence for the Interaction of Endophilin A3 with Endogenous Kca2.3 Channels in PC12 Cells

Author

Malika Janbein, Mohamed Abo Quader, Anselm Cornelius Hoppner, Isabell Grüner, Erich Wanker, Stephanie Wälter, Eva Küppers, Stephan Grissmer, and Heike Jäger

Subjects
KCa2.3 channel, Endophilin A3, Protein-protein-interaction, Yeast two-hybrid experiments, Pull-down assays, Electrophysiology, Ca2+ Measurements, Physiology, QP1-981, Biochemistry, QD415-436
Abstract

Background/Aims: Small-conductance calcium-activated (SK) channels play an important role by controlling the after-hyperpolarization of excitable cells. The level of expression and density of these channels is an essential factor for controlling different cellular functions. Several studies showed a co-localization of KCa2.3 channels and Endophilin A3 in different tissues. Endophilin A3 belongs to a family of BAR- and SH3 domain containing proteins that bind to dynamin and are involved in the process of vesicle scission in clathrin-mediated endocytosis. Methods: Using the yeast two-hybrid system and the GST pull down assay we demonstrated that Endophilin A3 interacts with the N-terminal part of KCa2.3 channels. In addition, we studied the impact of this interaction on channel activity by patch clamp measurements in PC12 cells expressing endogenous KCa2.3 channels. KCa2.3 currents were activated by using pipette solutions containing 1 µM free Ca2+. Results: Whole-cell measurements of PC12 cells transfected with Endophilin A3 showed a reduction of KCa2.3 specifc Cs+ currents indicating that the interaction of Endophilin A3 with KCa2.3 channels also occurs in mammalian cells and that this interaction has functional consequences for current flowing through KCa2.3 channels. Since KCa2.3 specific currents could be increased in PC12 cells transfected with Endophilin A3 with DC-EBIO (30 µM), a known SK-channel activator, these data also implicate that Endophilin A3 did not significantly remove KCa2.3 channels from the membrane but changed the sensitivity of the channels to Ca2+ which could be overcome by DC-EBIO. Conclusion: This interaction seems to be important for the function of KCa2.3 channels and might therefore play a significant role in situations where channel activation is pivotal for cellular function.

Published
2014
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5. Voltage-gated potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Author

Xiaoliang Wang, James S. Trimmer, Walter Stühmer, Michael C. Sanguinetti, Bernardo Rudy, Gail A. Robertson, Luis A. Pardo, Jeanne Nerbonne, David Mckinnon, Michel Lazdunski, Lily Y. Jan, George A. Gutman, Stephan Grissmer, M. Hunter Giese, K. George Chandy, and Bernard Attali

Abstract

The 6TM family of K channels comprises the voltage-gated KV subfamilies, the EAG subfamily (which includes hERG channels), the Ca2+-activated Slo subfamily (actually with 7TM, termed BK) and the Ca2+-activated SK subfamily. These channels possess a pore-forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. Kv1.1 with Kv1.2; Kv7.2 with Kv7.3). The pharmacology largely reflects the subunit composition of the functional channel.

Published
2023

6. Calcium- and sodium-activated potassium channels (KCa, KNa) in GtoPdb v.2023.1

Author

Heike Wulff, Aguan D. Wei, Leonard K. Kaczmarek, George A. Gutman, Stephan Grissmer, K. George Chandy, and Richard Aldrich

Subjects
General Medicine, General Chemistry
Abstract

Calcium- and sodium- activated potassium channels are members of the 6TM family of K channels which comprises the voltage-gated KV subfamilies, including the KCNQ subfamily, the EAG subfamily (which includes hERG channels), the Ca2+-activated Slo subfamily (actually with 6 or 7TM) and the Ca2+- and Na+-activated SK subfamily (nomenclature as agreed by the NC-IUPHAR Subcommittee on Calcium- and sodium-activated potassium channels [126]). As for the 2TM family, the pore-forming a subunits form tetramers and heteromeric channels may be formed within subfamilies (e.g. KV1.1 with KV1.2; KCNQ2 with KCNQ3).

Published
2023
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7. Voltage-gated potassium channels (Kv) in GtoPdb v.2023.1

Author

Xiaoliang Wang, James S. Trimmer, Walter Stühmer, Michael C. Sanguinetti, Bernardo Rudy, Gail A. Robertson, Luis A. Pardo, Jeanne Nerbonne, David Mckinnon, Michel Lazdunski, Lily Y. Jan, George A. Gutman, Stephan Grissmer, M. Hunter Giese, K. George Chandy, and Bernard Attali

Subjects
General Medicine, General Chemistry
Abstract

The 6TM family of K channels comprises the voltage-gated KV subfamilies, the EAG subfamily (which includes hERG channels), the Ca2+-activated Slo subfamily (actually with 7TM, termed BK) and the Ca2+-activated SK subfamily. These channels possess a pore-forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. Kv1.1 with Kv1.2; Kv7.2 with Kv7.3). The pharmacology largely reflects the subunit composition of the functional channel.Kv7 channelsKv7.1-Kv7.5 (KCNQ1-5) K+ channels are voltage-gated K+ channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K+ currents, such as the neuronal M-current and the cardiac IKs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, autism spectrum disorders, cardiac arrhythmias and deafness. Thanks to the recent knowledge of the structure and function of human KCNQ-encoded proteins, these channels are increasingly used as drug targets for treating diseases [326, 2, 767].

Published
2023
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8. THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels

Author

Chandy George, Israel Hanukoglu, Aguan D. Wei, Jane F. Armstrong, John A. Peters, Roslyn M. Bill, Steve A.N. Goldstein, Lucia G. Sivilotti, Mootaz M. Salman, Heike Wulff, Paul Davies, Michael Zhu, Stephan Kellenberger, Elena Faccenda, Michael F. Jarvis, Dejian Ren, Stefanie Fenske, Emma L. Veale, Jörg Striessnig, Verena Hammelmann, Brian F. King, Terrance P. Snutch, Trevor G. Smart, Leonard K. Kaczmarek, Brenda T. Winn, Eamonn Kelly, Philip Kitchen, Richard W. Aldrich, Jamie A. Davies, Charlotte Van den Eynde, Lachlan D. Rash, Edward Perez-Reyes, Elvir Becirovic, Christopher Southan, Joris Vriens, William A. Catterall, Jinbin Tian, Martin Biel, Adam J. Pawson, Leigh D. Plant, Alistair Mathie, Kotdaji Ha, James S. Trimmer, Bernard Attali, Anders A. Jensen, Lixia Yue, Joseph W. Lynch, Austin M. Baggetta, Haoxing Xu, Charles Kennedy, Xiaoli Zhang, Stephen P.H. Alexander, Simon D. Harding, Markus Delling, Simonetta Falzoni, Stephan Grissmer, Francesco Di Virgilio, and Alex C. Conner

Subjects
RM, AMINOBUTYRIC ACID(A) RECEPTORS, Databases, Pharmaceutical, Computer science, Knowledge Bases, UNION-OF-PHARMACOLOGY, Pharmacology, Ligands, Ion Channels, Receptors, G-Protein-Coupled, law.invention, Humans, CELL-VOLUME REGULATION, law, Summary information, Pharmacology & Pharmacy, NICOTINIC ACETYLCHOLINE-RECEPTOR, CA2+-ACTIVATED K+ CHANNELS, Science & Technology, Clinical pharmacology, IONOTROPIC GLUTAMATE RECEPTORS, HUMAN 5-HYDROXYTRYPTAMINE(3) RECEPTOR, ACTIVATED POTASSIUM CHANNEL, VOLTAGE-GATED SODIUM, Catalytic receptors, Life Sciences & Biomedicine, CYCLIC ADP-RIBOSE
Abstract

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15539. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate. ispartof: BRITISH JOURNAL OF PHARMACOLOGY vol:178 pages:S157-S245 ispartof: location:England status: published

Published
2021
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9. Calcium- and sodium-activated potassium channels (KCa, KNa) in GtoPdb v.2021.3

Author

Stephan Grissmer, Aguan D. Wei, Leonard K. Kaczmarek, Richard W. Aldrich, George A. Gutman, K. George Chandy, and Heike Wulff

Subjects
Subfamily, biology, Chemistry, Stereochemistry, Sodium, hERG, biology.protein, chemistry.chemical_element, Calcium, Potassium channel, K channels
Abstract

Calcium- and sodium- activated potassium channels are members of the 6TM family of K channels which comprises the voltage-gated KV subfamilies, including the KCNQ subfamily, the EAG subfamily (which includes hERG channels), the Ca2+-activated Slo subfamily (actually with 6 or 7TM) and the Ca2+- and Na+-activated SK subfamily (nomenclature as agreed by the NC-IUPHAR Subcommittee on Calcium- and sodium-activated potassium channels [125]). As for the 2TM family, the pore-forming a subunits form tetramers and heteromeric channels may be formed within subfamilies (e.g. KV1.1 with KV1.2; KCNQ2 with KCNQ3).

Published
2021
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10. Voltage-gated potassium channels (Kv) in GtoPdb v.2021.3

Author

Bernardo Rudy, Bernard Attali, Lily Yeh Jan, Xiaoliang Wang, M. Hunter Giese, James S. Trimmer, David McKinnon, George A. Gutman, Jeanne M. Nerbonne, Michel Lazdunski, Stephan Grissmer, Walter Stühmer, K. George Chandy, Gail A. Robertson, Luis A. Pardo, and Michael C. Sanguinetti

Subjects
Α subunit, Subfamily, biology, Chemistry, Stereochemistry, Protein subunit, hERG, biology.protein, Homomeric, Voltage-gated potassium channel, K channels
Abstract

The 6TM family of K channels comprises the voltage-gated KV subfamilies, the EAG subfamily (which includes hERG channels), the Ca2+-activated Slo subfamily (actually with 7TM, termed BK) and the Ca2+-activated SK subfamily. These channels possess a pore-forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. Kv1.1 with Kv1.2; Kv7.2 with Kv7.3). The pharmacology largely reflects the subunit composition of the functional channel.

Published
2021
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11. 20 Vestibuläres System

Author

Jens Rettig, Erhard Wischmeyer, Rainer Deutzmann, Heimo Ehmke, Jan C. Behrends, Jens Leipziger, Claudia Pedain, Markus Hoth, Stephan Frings, Frank Müller, Stephan Grissmer, Armin Kurtz, Charlotte Wagner, and Josef Bischofberger

Published
2021
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12. 7 Immunsystem Immunsystem

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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14. 6 Blut Blut

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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16. Sachverzeichnis

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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17. 13 Ernährung, Verdauung und Absorption, Leber

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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18. Duale Reihe Physiologie

Author

Jan C. Behrends, Erhard Wischmeyer, Heimo Ehmke, Charlotte Wagner, Claudia Pedain, Markus Hoth, Josef Bischofberger, Stephan Frings, Stephan Grissmer, Frank Müller, Jens Rettig, Armin Kurtz, Jens Leipziger, and Rainer Deutzmann

Published
2021
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19. 10 Niere und Salz-/Wasserhaushalt Niere

Author

Rainer Deutzmann, Jan C. Behrends, Frank Müller, Jens Leipziger, Charlotte Wagner, Josef Bischofberger, Jens Rettig, Armin Kurtz, Heimo Ehmke, Erhard Wischmeyer, Claudia Pedain, Markus Hoth, Stephan Frings, and Stephan Grissmer

Published
2021
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20. Vorwort

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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21. 5 Blutkreislauf Blutkreislauf

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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22. 9 Säure-Basen-Haushalt Säure-Basen-Haushalt

Author

Jens Leipziger, Jens Rettig, Charlotte Wagner, Josef Bischofberger, Rainer Deutzmann, Jan C. Behrends, Claudia Pedain, Markus Hoth, Stephan Frings, Stephan Grissmer, Armin Kurtz, Erhard Wischmeyer, Heimo Ehmke, and Frank Müller

Published
2021
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23. 1 Grundlagen der Zellphysiologie Zellphysiologie

Author

Rainer Deutzmann, Jan C. Behrends, Jens Rettig, Charlotte Wagner, Josef Bischofberger, Claudia Pedain, Markus Hoth, Frank Müller, Stephan Frings, Heimo Ehmke, Stephan Grissmer, Erhard Wischmeyer, Jens Leipziger, and Armin Kurtz

Published
2021
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24. 4 Herz Herz

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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25. 22 Sensomotorik Sensomotorik

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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26. 11 Hormonelle Regulation Hormone Regulation

Author

Rainer Deutzmann, Jan C. Behrends, Jens Rettig, Claudia Pedain, Markus Hoth, Stephan Frings, Frank Müller, Erhard Wischmeyer, Heimo Ehmke, Stephan Grissmer, Charlotte Wagner, Josef Bischofberger, Jens Leipziger, and Armin Kurtz

Published
2021
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28. 24 Antwortkommentare klinische Fallbeispiele

Author

Claudia Pedain, Charlotte Wagner, Markus Hoth, Josef Bischofberger, Stephan Frings, Rainer Deutzmann, Jan C. Behrends, Jens Rettig, Frank Müller, Stephan Grissmer, Armin Kurtz, Jens Leipziger, Erhard Wischmeyer, and Heimo Ehmke

Published
2021
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29. 3 Grundlagen der Muskelphysiologie

Author

Rainer Deutzmann, Jan C. Behrends, Armin Kurtz, Jens Leipziger, Claudia Pedain, Markus Hoth, Stephan Frings, Heimo Ehmke, Charlotte Wagner, Josef Bischofberger, Stephan Grissmer, Erhard Wischmeyer, Frank Müller, and Jens Rettig

Published
2021
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30. 8 Atmung Atmung

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2021
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32. Kinetic Aspects of Verapamil Binding (On-Rate) on Wild-Type and Six hKv1.3 Mutant Channels

Author

Stephan Grissmer and Ann-Kathrin Diesch

Subjects
0301 basic medicine, Patch-Clamp Techniques, Physiology, Mutant, Kv1.3 channel, lcsh:Physiology, Membrane Potentials, lcsh:Biochemistry, 03 medical and health sciences, Chlorocebus aethiops, medicine, Potassium Channel Blockers, Animals, Humans, lcsh:QD415-436, Patch clamp, Amino Acid Sequence, Potassium channel, Membrane potential, Binding Sites, Kv1.3 Potassium Channel, lcsh:QP1-981, Chemistry, Wild type, Potassium channel blocker, Protein Structure, Tertiary, Molecular Docking Simulation, Electrophysiology, Kinetics, 030104 developmental biology, Verapamil, COS Cells, Biophysics, Mutagenesis, Site-Directed, Patch-clamp, Open channel block, medicine.drug, Protein Binding
Abstract

Background/Aims: The human-voltage gated Kv1.3 channel (hKv1.3) is expressed in T- and B lymphocytes. Verapamil is able to block hKv1.3 channels. We characterized the effect of verapamil on currents through hKv1.3 channels paying special attention to the on-rate (kon) of verapamil. By comparing on-rates obtained in wild-type (wt) and mutant channels a binding pocket for verapamil and impacts of different amino acid residues should be investigated. Methods: Using the whole-cell patch clamp technique the action of verapamil on currents through wild-type and six hKv1.3 mutant channels in the open state was investigated by measuring the time course of the open channel block in order to calculate kon of verapamil. Results: The on-rate of verapamil to block current through hKv1.3_T419C mutant channels is similar to that obtained for hKv1.3_wt channels whereas the on-rate of verapamil to block currents through hKv1.3_L417C and hKv1.3_L418C mutant channels was ∼ 3 times slower compared to in wt channels. The on-rate of verapamil to block currents through hKv1.3_L346C and the double mutant hKv1.3_L346C_L418C channel was ∼ 2 times slower compared to that obtained in the wt channel. The hKv1.3_I420C mutant channel reduced the on-rate of verapamil to block currents ∼ 6 fold. Conclusions: We conclude that position 420 in hKv1.3 channels maximally interferes with verapamil reaching its binding site to block the channel. Positions 417 and 418 in hKv1.3 channels partially hinder verapamil reaching its binding site to block the channel whereas position 419 may not interfere with verapamil at all. Mutant hKv1.3_L346C and hKv1.3_L346C_L418C mutant channels might indirectly influence the ability of verapamil reaching its binding site to block current.

Published
2017

33. Calcium- and sodium-activated potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Author

Heike Wulff, Leonard K. Kaczmarek, George A. Gutman, Aguan D. Wei, Richard W. Aldrich, K. George Chandy, and Stephan Grissmer

Subjects
Subfamily, biology, Chemistry, Stereochemistry, Sodium, hERG, biology.protein, chemistry.chemical_element, Calcium, Potassium channel, K channels
Abstract

Calcium- and sodium- activated potassium channels are members of the 6TM family of K channels which comprises the voltage-gated KV subfamilies, including the KCNQ subfamily, the EAG subfamily (which includes herg channels), the Ca2+-activated Slo subfamily (actually with 6 or 7TM) and the Ca2+- and Na+-activated SK subfamily (nomenclature as agreed by the NC-IUPHAR Subcommittee on Calcium- and sodium-activated potassium channels [124]). As for the 2TM family, the pore-forming a subunits form tetramers and heteromeric channels may be formed within subfamilies (e.g. KV1.1 with KV1.2; KCNQ2 with KCNQ3).

Published
2019
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34. International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels

Author

K. George Chandy, Leonard K. Kaczmarek, Aguan Wei, Stephan Grissmer, Richard W. Aldrich, Heike Wulff, Ohlstein, Eliot H, and Lee Kong Chian School of Medicine (LKCMedicine)

Subjects
Male, 0301 basic medicine, BK channel, Potassium Channels, Subfamily, 1.1 Normal biological development and functioning, Sodium, chemistry.chemical_element, Gating, Calcium, Na+ and Cl−, Potassium Channels, Calcium-Activated, 03 medical and health sciences, 0302 clinical medicine, Chlorides, Underpinning research, Terminology as Topic, Animals, Humans, Science::Medicine [DRNTU], Pharmacology & Pharmacy, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Ion channel, Pharmacology, Calcium metabolism, biology, Chemistry, Pharmacology and Pharmaceutical Sciences, Intermediate-Conductance Calcium-Activated Potassium Channels, Spermatozoa, Potassium channel, Calcium-Activated, 030104 developmental biology, Ca2+-activated, Biochemistry, biology.protein, Molecular Medicine, Ion Channel Gating, 030217 neurology & neurosurgery
Abstract

© 2016 by The Author(s). Asubset of potassium channels is regulated primarily by changes in the cytoplasmic concentration of ions, including calcium, sodium, chloride, and protons. The eight members of this subfamily were originally all designated as calcium-activated channels. More recent studies have clarified the gating mechanisms for these channels and have documented that not allmembers are sensitive to calcium. This article describes themolecular relationships between these channels and provides an introduction to their functional properties. It also introduces a new nomenclature that differentiates between calcium- and sodium-activated potassium channels.

Published
2016
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35. 22 Sensomotorik

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2017
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36. 10 Niere und Salz-/Wasserhaushalt (I)

Author

Frank Müller, Jens Leipziger, Rainer Deutzmann, Heimo Ehmke, Jan C. Behrends, Erhard Wischmeyer, Armin Kurtz, Charlotte Wagner, Josef Bischofberger, Jens Rettig, Stephan Grissmer, Claudia Pedain, Markus Hoth, and Stephan Frings

Published
2017
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37. 15 Arbeits-, Sport- und Leistungsphysiologie

Author

Rainer Deutzmann, Jan C. Behrends, Heimo Ehmke, Jens Rettig, Claudia Pedain, Markus Hoth, Stephan Frings, Frank Müller, Erhard Wischmeyer, Stephan Grissmer, Jens Leipziger, Charlotte Wagner, Josef Bischofberger, and Armin Kurtz

Published
2017
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39. 11 Hormonelle Regulation (I)

Author

Claudia Pedain, Markus Hoth, Stephan Frings, Armin Kurtz, Erhard Wischmeyer, Frank Müller, Jens Leipziger, Heimo Ehmke, Jens Rettig, Charlotte Wagner, Josef Bischofberger, Rainer Deutzmann, Jan C. Behrends, and Stephan Grissmer

Published
2017
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40. Vorwort

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2017
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41. 18 Visuelles System

Author

Rainer Deutzmann, Jan C. Behrends, Charlotte Wagner, Josef Bischofberger, Claudia Pedain, Markus Hoth, Stephan Frings, Jens Leipziger, Jens Rettig, Stephan Grissmer, Frank Müller, Armin Kurtz, Heimo Ehmke, and Erhard Wischmeyer

Published
2017
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43. 14 Energie- und Wärmehaushalt

Author

Claudia Pedain, Markus Hoth, Stephan Grissmer, Stephan Frings, Erhard Wischmeyer, Rainer Deutzmann, Jens Rettig, Jan C. Behrends, Frank Müller, Heimo Ehmke, Charlotte Wagner, Josef Bischofberger, Jens Leipziger, and Armin Kurtz

Published
2017
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44. 9 Säure-Basen-Haushalt

Author

Jens Rettig, Rainer Deutzmann, Jan C. Behrends, Armin Kurtz, Jens Leipziger, Heimo Ehmke, Charlotte Wagner, Josef Bischofberger, Stephan Grissmer, Erhard Wischmeyer, Claudia Pedain, Markus Hoth, Stephan Frings, and Frank Müller

Published
2017
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45. 5 Blutkreislauf (I)

Author

Jens Rettig, Rainer Deutzmann, Jens Leipziger, Jan C. Behrends, Stephan Grissmer, Heimo Ehmke, Claudia Pedain, Markus Hoth, Charlotte Wagner, Stephan Frings, Josef Bischofberger, Armin Kurtz, Frank Müller, and Erhard Wischmeyer

Published
2017
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46. 6 Blut

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2017
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47. 4 Herz (I)

Author

Jens Rettig, Jens Leipziger, Claudia Pedain, Markus Hoth, Stephan Frings, Erhard Wischmeyer, Heimo Ehmke, Rainer Deutzmann, Frank Müller, Jan C. Behrends, Armin Kurtz, Stephan Grissmer, Charlotte Wagner, and Josef Bischofberger

Published
2017
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48. 2 Grundlagen der Neurophysiologie

Author

Jens Rettig, Erhard Wischmeyer, Rainer Deutzmann, Claudia Pedain, Markus Hoth, Jan C. Behrends, Stephan Frings, Frank Müller, Stephan Grissmer, Charlotte Wagner, Armin Kurtz, Josef Bischofberger, Heimo Ehmke, and Jens Leipziger

Published
2017
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49. 13 Ernährung, Verdauung und Absorption, Leber (I)

Author

Armin Kurtz, Erhard Wischmeyer, Rainer Deutzmann, Jan C. Behrends, Jens Leipziger, Jens Rettig, Heimo Ehmke, Charlotte Wagner, Josef Bischofberger, Stephan Grissmer, Claudia Pedain, Markus Hoth, Frank Müller, and Stephan Frings

Published
2017
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50. Sachverzeichnis

Author

Jan C. Behrends, Josef Bischofberger, Rainer Deutzmann, Heimo Ehmke, Stephan Frings, Stephan Grissmer, Markus Hoth, Armin Kurtz, Jens Leipziger, Frank Müller, Claudia Pedain, Jens Rettig, Charlotte Wagner, and Erhard Wischmeyer

Published
2017
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