The 1997 Stevenson Award Lecture. Cardiac K+channel gating: cloned delayed rectifier mechanisms and drug modulation

1998 ◽  
Vol 76 (2) ◽  
pp. 77-89 ◽  
Author(s):  
David Fedida ◽  
Fred SP Chen ◽  
Xue Zhang
Keyword(s):  
Channel Gating ◽  
State Dependence ◽  
Structural Features ◽  
K Channel ◽  
Delayed Rectifier ◽  
Specific Reference ◽  
Channel Blockers ◽  
Antiarrhythmic Agents ◽  
Gating Currents ◽  
Voltage Gated

K+ channels are ubiquitous membrane proteins, which have a central role in the control of cell excitability. In the heart, voltage-gated delayed rectifier K+ channels, like Kv1.5, determine repolarization and the cardiac action potential plateau duration. Here we review the broader properties of cloned voltage-gated K+ channels with specific reference to the hKv1.5 channel in heart. We discuss the basic structural components of K+ channels such as the pore, voltage sensor, and fast inactivation, all of which have been extensively studied. Slow, or C-type, inactivation and the structural features that control pore opening are less well understood, although recent studies have given new insight into these problems. Information about channel transitions that occur prior to opening is provided by gating currents, which reflect charge-carrying transitions between kinetic closed states. By studying modulation of the gating properties of K+ channels by cations and with drugs, we can make a more complete interpretation of the state dependence of drug and ion interactions with the channel. In this way we can uncover the detailed mechanisms of action of K+ channel blockers such as tetraethylammonium ions and 4-aminopyridine, and antiarrhythmic agents such as nifedipine and quinidine.Key words: potassium channel, Kv1.5, channel gating, inactivation, pore region, gating currents.

scholarly journals Modification of potassium channel kinetics by amino group reagents.

1992 ◽  
Vol 99 (1) ◽  
pp. 109-129 ◽  
Author(s):  
S Spires ◽  
T Begenisich
Keyword(s):  
Channel Gating ◽  
Ionic Currents ◽  
K Channel ◽  
Delayed Rectifier ◽  
Trinitrobenzene Sulfonic Acid ◽  
Voltage Sensitivity ◽  
Amino Group ◽  
Amino Groups ◽  
Gating Currents ◽  
Simple Kinetic Model

We have examined the actions of several amino group reagents on delayed rectifier potassium channels in squid giant axons. Three general classes of reagents were used: (1) those that preserved the positive charge of amino groups; (2) those that neutralize the charge; and (3) those that replace the positive with a negative charge. All three types of reagents produced qualitatively similar effects on K channel properties. Trinitrobenzene sulfonic acid (TNBS) neutralizes the peptide terminal amino groups and the epsilon-amino group of lysine groups. TNBS (a) slowed the kinetics of macroscopic ionic currents; (b) increased the size of ionic currents at large positive voltages; (c) shifted the voltage-dependent probability of channel opening to more positive potentials but had no effect on the voltage sensitivity; and (d) altered several properties of K channel gating currents. The actions of TNBS on gating currents suggest the presence of multiple gating current components. These effects are not all coupled, suggesting that several amino groups on the external surface of K channels are important for channel gating. A simple kinetic model that considers the channel to be composed of independent heterologous subunits is consistent with most of the modifications produced by amino group reagents.

Dynamic regulation of the voltage-gated Kv2.1 potassium channel by multisite phosphorylation

2007 ◽  
Vol 35 (5) ◽  
pp. 1064-1068 ◽  
Author(s):  
D.P. Mohapatra ◽  
K.-S. Park ◽  
J.S. Trimmer
Keyword(s):  
Neuronal Excitability ◽  
Critical Role ◽  
Functional Characterization ◽  
K Channel ◽  
Delayed Rectifier ◽  
Dynamic Regulation ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Specific Regulation

Voltage-gated K+ channels are key regulators of neuronal excitability. The Kv2.1 voltage-gated K+ channel is the major delayed rectifier K+ channel expressed in most central neurons, where it exists as a highly phosphorylated protein. Kv2.1 plays a critical role in homoeostatic regulation of intrinsic neuronal excitability through its activity- and calcineurin-dependent dephosphorylation. Here, we review studies leading to the identification and functional characterization of in vivo Kv2.1 phosphorylation sites, a subset of which contribute to graded modulation of voltage-dependent gating. These findings show that distinct developmental-, cell- and state-specific regulation of phosphorylation at specific sites confers a diversity of functions on Kv2.1 that is critical to its role as a regulator of intrinsic neuronal excitability.

scholarly journals Properties of the Voltage-Gated Proton Channel Gating Currents

2018 ◽  
Vol 114 (3) ◽  
pp. 546a ◽  
Author(s):  
Emerson M. Carmona ◽  
David Baez-Nieto ◽  
Amaury Pupo ◽  
Karen Castillo ◽  
Osvaldo Alvarez ◽  
...  
Keyword(s):  
Channel Gating ◽  
Proton Channel ◽  
Gating Currents ◽  
Voltage Gated

Complexity of the outward K+ current of the rat megakaryocyte

1997 ◽  
Vol 272 (5) ◽  
pp. C1525-C1531 ◽  
Author(s):  
E. Romero ◽  
R. Sullivan
Keyword(s):  
K Channel ◽  
Delayed Rectifier ◽  
Channel Blockers ◽  
Excitable Cells ◽  
Electrophysiological Properties ◽  
Relative Contribution ◽  
Delayed Rectifier Current ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
K Current

Megakaryocytes isolated from rat bone marrow express a voltage-dependent, outward K+ current with complex kinetics of activation and inactivation. We found that this current could be separated into at least two components based on differential responses to K+ channel blockers. One component, which exhibited features of the "transient" or "A-type" K+ current of excitable cells, was more strongly blocked by 4-aminopyridine (4-AP) than by tetrabutylammonium (TBA). This current, which we designated as "4-AP-sensitive" current, activated rapidly at potentials more positive than -40 mV and subsequently underwent rapid voltage-dependent inactivation. A separate current that activated slowly was blocked much more effectively by TBA than by 4-AP. This "TBA-sensitive" component, which resembled a typical delayed rectifier current, was much more resistant to voltage-dependent inactivation. The relative contribution of each of these components varied from cell to cell. The effect of charybdotoxin was similar to that of 4-AP. Our data indicate that the voltage-dependent K+ current of resting megakaryocytes is more complex than heretofore believed and support the emerging concept that megakaryocytes possess intricate electrophysiological properties.

scholarly journals State-dependent Block of CNG Channels by Dequalinium

2004 ◽  
Vol 123 (3) ◽  
pp. 295-304 ◽  
Author(s):  
Tamara Rosenbaum ◽  
Ariela Gordon-Shaag ◽  
León D. Islas ◽  
Jeremy Cooper ◽  
Mika Munari ◽  
...  
Keyword(s):  
Specific Effect ◽  
State Dependence ◽  
Open Channels ◽  
K Channel ◽  
Channel Blockers ◽  
Ion Permeation ◽  
High Permeability ◽  
Nonselective Cation Channels ◽  
State Dependent ◽  
Small Conductance

Cyclic nucleotide–gated (CNG) ion channels are nonselective cation channels with a high permeability for Ca2+. Not surprisingly, they are blocked by a number of Ca2+ channel blockers including tetracaine, pimozide, and diltiazem. We studied the effects of dequalinium, an extracellular blocker of the small conductance Ca2+-activated K+ channel. We previously noted that dequalinium is a high-affinity blocker of CNGA1 channels from the intracellular side, with little or no state dependence at 0 mV. Here we examined block by dequalinium at a broad range of voltages in both CNGA1 and CNGA2 channels. We found that dequalinium block was mildly state dependent for both channels, with the affinity for closed channels 3–5 times higher than that for open channels. Mutations in the S4-S5 linker did not alter the affinity of open channels for dequalinium, but increased the affinity of closed channels by 10–20-fold. The state-specific effect of these mutations raises the question of whether/how the S4-S5 linker alters the binding of a blocker within the ion permeation pathway.

Voltage clamp fluorimetry studies of mammalian voltage-gated K+ channel gating

2007 ◽  
Vol 35 (5) ◽  
pp. 1080-1082 ◽  
Author(s):  
T.W. Claydon ◽  
D. Fedida
Keyword(s):  
Ion Channel ◽  
Potassium Channel ◽  
Real Time ◽  
Voltage Clamp ◽  
Conformational Changes ◽  
Channel Gating ◽  
K Channel ◽  
Voltage Gated ◽  
Kv Channels ◽  
Health And Disease

VCF (voltage clamp fluorimetry) provides a powerful technique to observe real-time conformational changes that are associated with ion channel gating. The present review highlights the insights such experiments have provided in understanding Kv (voltage-gated potassium) channel gating, with particular emphasis on the study of mammalian Kv1 channels. Further applications of VCF that would contribute to our understanding of the modulation of Kv channels in health and disease are also discussed.

scholarly journals Structure-activity relationship studies of three novel 4-aminopyridine K+ channel blockers

2019 ◽  
Author(s):  
Sofia Rodríguez-Rangel ◽  
Alyssa D. Bravin ◽  
Karla M. Ramos-Torres ◽  
Pedro Brugarolas ◽  
Jorge E. Sánchez-Rodríguez
Keyword(s):  
Multiple Sclerosis ◽  
Potassium Channels ◽  
Symptomatic Treatment ◽  
K Channel ◽  
Channel Blockers ◽  
Rodent Models ◽  
Voltage Gated ◽  
Structure Activity ◽  
Pet Tracer ◽  
Ph Conditions

Abstract4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate three novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) and trifluoromethyl (-CF3) in the 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (pKa and logD) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that all three derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP, whereas the methoxy (3MeO4AP) and trifluoromethyl (3CF34AP) containing compounds were about 3- to 4-fold less potent than 4AP, respectively. These results suggest that these novel derivatives are potential candidates for therapy and imaging.

scholarly journals The myth of scorpion suicide: are scorpions insensitive to their own venom?

1998 ◽  
Vol 201 (18) ◽  
pp. 2625-2636
Author(s):  
C Legros ◽  
MF Martin-Eauclaire ◽  
D Cattaert
Keyword(s):  
Action Potential ◽  
Procambarus Clarkii ◽  
Scorpion Venom ◽  
K Channel ◽  
Muscle Fibres ◽  
Channel Blockers ◽  
Na Channels ◽  
Nerve Fibres ◽  
K Channels ◽  
Voltage Gated

The resistance of the scorpion Androctonus australis to its own venom, as well as to the venom of other species, was investigated. A comparison of the electrical and pharmacological properties of muscle and nerve fibres from Androctonus australis with those from the crayfish Procambarus clarkii enabled us to understand the lack of effect of scorpion venom (110-180 microg ml-1) and purified toxins, which are active on voltage-gated Na+ and K+ channels, Ca2+-activated K+ channels, on scorpion tissues. Voltage-clamp experiments showed that peptide K+ channel blockers from scorpion and snake have no effect on currents in muscle and nerve fibres from either scorpions or crayfish. The scorpion toxin kaliotoxin (KTX), a specific blocker of Kv1.1 and Kv1.3 K+ channels, had no effect on muscle fibres of A. australis (2 micromol l-1) or P. clarkii (400 nmol l-1). Similarly, charybdotoxin (ChTX) had no effect on the muscle fibres of A. australis (10 micromol l-1) or P. clarkii (200 nmol l-1) and neither did the snake toxin dendrotoxin (DTX) at concentrations of 100 nmol l-1 in A. australis and 200 nmol l-1 in P. clarkii. These three toxins (KTX, ChTX and DTX) did not block K+ currents recorded from nerve fibres in P. clarkii. The pharmacology of the K+ channels in these two arthropods did not conform to that previously described for K+ channels in other species. Current-clamp experiments clearly indicated that the venom of A. australis (50 microg ml-1) had no effect on the shape of the action potential recorded from nerve cord axons from A. australis. At a concentration of 50 microg ml-1, A. australis venom greatly prolonged the action potential in the crayfish giant axon. The absence of any effect of the anti-mammal <IMG src="/images/symbols/&agr ;.gif" WIDTH="9" HEIGHT="12" ALIGN="BOTTOM" NATURALSIZEFLAG="3">-toxin AaH II (100 nmol l-1) and the anti-insect toxin AaH IT1 (100 nmol l-1) on scorpion nerve fibres revealed strong pharmacological differences between the voltage-gated Na+ channels of scorpion and crayfish. We conclude that the venom from A. australis is pharmacologically inactive on K+ channels and on voltage-sensitive Na+ channels from this scorpion.

scholarly journals Direct Interaction of a Brain Voltage-Gated K+Channel with Syntaxin 1A: Functional Impact on Channel Gating

2001 ◽  
Vol 21 (6) ◽  
pp. 1964-1974 ◽  
Author(s):  
Oded Fili ◽  
Itzhak Michaelevski ◽  
Yaniv Bledi ◽  
Dodo Chikvashvili ◽  
Dafna Singer-Lahat ◽  
...  
Keyword(s):  
Channel Gating ◽  
Direct Interaction ◽  
K Channel ◽  
Syntaxin 1A ◽  
Functional Impact ◽  
Voltage Gated
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