Functional Modulation of Cardiac ATP-Sensitive K+ Channels

Physiology ◽  
1998 ◽  
Vol 13 (3) ◽  
pp. 131-137 ◽  
Author(s):  
Masayasu Hiraoka ◽  
Tetsushi Furukawa
Keyword(s):  
Action Potential ◽  
Channel Activity ◽  
K Channels ◽  
Channel Function ◽  
Intracellular Atp ◽  
Functional Modulation ◽  
Action Potential Shortening

ATP-sensitive K+ (KATP) channels are inhibited by intracellular ATP, but MgATP is necessary to maintain the channel activity. Numerous cofactors modulate channel function. K+ channel openers activate and sulfonylureas inhibit KATP channels. The structure of cardiac KATP channel is a complex of mainly KIR6.2 and SUR2a. Activation of cardiac KATP channels contributes to action potential shortening during ischemia and plays a role in cardioprotection.

scholarly journals Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain

2016 ◽  
Vol 113 (35) ◽  
pp. 9916-9921 ◽  
Author(s):  
Carol A. Harley ◽  
Greg Starek ◽  
David K. Jones ◽  
Andreia S. Fernandes ◽  
Gail A. Robertson ◽  
...  
Keyword(s):  
Action Potential ◽  
Critical Role ◽  
Herg Channel ◽  
Pas Domain ◽  
Channel Activity ◽  
Single Chain ◽  
Orphan Receptors ◽  
Human Cardiomyocytes ◽  
Channel Function ◽  
Single Chain Variable Fragments

The human human ether-à-go-go–related gene (hERG) potassium channel plays a critical role in the repolarization of the cardiac action potential. Changes in hERG channel function underlie long QT syndrome (LQTS) and are associated with cardiac arrhythmias and sudden death. A striking feature of this channel and KCNH channels in general is the presence of an N-terminal Per-Arnt-Sim (PAS) domain. In other proteins, PAS domains bind ligands and modulate effector domains. However, the PAS domains of KCNH channels are orphan receptors. We have uncovered a family of positive modulators of hERG that specifically bind to the PAS domain. We generated two single-chain variable fragments (scFvs) that recognize different epitopes on the PAS domain. Both antibodies increase the rate of deactivation but have different effects on channel activation and inactivation. Importantly, we show that both antibodies, on binding to the PAS domain, increase the total amount of current that permeates the channel during a ventricular action potential and significantly reduce the action potential duration recorded in human cardiomyocytes. Overall, these molecules constitute a previously unidentified class of positive modulators and establish that allosteric modulation of hERG channel function through ligand binding to the PAS domain can be attained.

scholarly journals Intracellular ATP Increases Capsaicin-Activated Channel Activity by Interacting with Nucleotide-Binding Domains

2000 ◽  
Vol 20 (22) ◽  
pp. 8298-8304 ◽  
Author(s):  
Jiyeon Kwak ◽  
Myeong Hyeon Wang ◽  
Sun Wook Hwang ◽  
Tae-Yoon Kim ◽  
Soon-Youl Lee ◽  
...  
Keyword(s):  
Nucleotide Binding ◽  
Channel Activity ◽  
Intracellular Atp ◽  
Binding Domains

scholarly journals Membrane-delimited Inhibition of Maxi-K Channel Activity by the Intermediate Conductance Ca2+-activated K Channel

2006 ◽  
Vol 127 (2) ◽  
pp. 159-169 ◽  
Author(s):  
Jill Thompson ◽  
Ted Begenisich
Keyword(s):  
Single Channel ◽  
Expression System ◽  
Chemical Activation ◽  
K Channel ◽  
Channel Activity ◽  
Single Family ◽  
Open Probability ◽  
K Channels ◽  
Channel Proteins ◽  
K Activity

The complexity of mammalian physiology requires a diverse array of ion channel proteins. This diversity extends even to a single family of channels. For example, the family of Ca2+-activated K channels contains three structural subfamilies characterized by small, intermediate, and large single channel conductances. Many cells and tissues, including neurons, vascular smooth muscle, endothelial cells, macrophages, and salivary glands express more than a single class of these channels, raising questions about their specific physiological roles. We demonstrate here a novel interaction between two types of Ca2+-activated K channels: maxi-K channels, encoded by the KCa1.1 gene, and IK1 channels (KCa3.1). In both native parotid acinar cells and in a heterologous expression system, activation of IK1 channels inhibits maxi-K activity. This interaction was independent of the mode of activation of the IK1 channels: direct application of Ca2+, muscarinic receptor stimulation, or by direct chemical activation of the IK1 channels. The IK1-induced inhibition of maxi-K activity occurred in small, cell-free membrane patches and was due to a reduction in the maxi-K channel open probability and not to a change in the single channel current level. These data suggest that IK1 channels inhibit maxi-K channel activity via a direct, membrane-delimited interaction between the channel proteins. A quantitative analysis indicates that each maxi-K channel may be surrounded by four IK1 channels and will be inhibited if any one of these IK1 channels opens. This novel, regulated inhibition of maxi-K channels by activation of IK1 adds to the complexity of the properties of these Ca2+-activated K channels and likely contributes to the diversity of their functional roles.

Molecular physiology of cardiac potassium channels

1996 ◽  
Vol 76 (1) ◽  
pp. 49-67 ◽  
Author(s):  
K. K. Deal ◽  
S. K. England ◽  
M. M. Tamkun
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Single Channel ◽  
Resting Membrane Potential ◽  
Molecular Physiology ◽  
K Channels ◽  
Relative Contribution ◽  
Outward Currents ◽  
Important Challenge ◽  
Heterologous Expression Systems

The cardiac action potential results from the complex, but precisely regulated, movement of ions across the sarcolemmal membrane. Potassium channels represent the most diverse class of ion channels in heart and are the targets of several antiarrhythmic drugs. Potassium currents in the myocardium can be classified into one of two general categories: 1) inward rectifying currents such as IK1, IKACh, and IKATP; and 2) primarily voltage-gated currents such as IKs, IKr, IKp, IKur, and Ito. The inward rectifier currents regulate the resting membrane potential, whereas the voltage-activated currents control action potential duration. The presence of these multiple, often overlapping, outward currents in native cardiac myocytes has complicated the study of individual K+ channels; however, the application of molecular cloning technology to these cardiovascular K+ channels has identified the primary structure of these proteins, and heterologous expression systems have allowed a detailed analysis of the function and pharmacology of a single channel type. This review addresses the progress made toward understanding the complex molecular physiology of K+ channels in mammalian myocardium. An important challenge for the future is to determine the relative contribution of each of these cloned channels to cardiac function.

scholarly journals Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents.

1992 ◽  
Vol 100 (4) ◽  
pp. 573-591 ◽  
Author(s):  
D N Sheppard ◽  
M J Welsh
Keyword(s):  
Cystic Fibrosis ◽  
Voltage Dependence ◽  
K Channel ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
K Channels ◽  
Intracellular Atp ◽  
Cl Channel ◽  
Cl Channels ◽  
Cystic Fibrosis Transmembrane

The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that is regulated by cAMP-dependent phosphorylation and by intracellular ATP. Intracellular ATP also regulates a class of K+ channels that have a distinct pharmacology: they are inhibited by sulfonylureas and activated by a novel class of drugs called K+ channel openers. In search of modulators of CFTR Cl- channels, we examined the effect of sulfonylureas and K+ channel openers on CFTR Cl- currents in cells expressing recombinant CFTR. The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively. Inhibition by both agents showed little voltage dependence and developed slowly; > 90% inhibition occurred 3 min after adding 1 mM tolbutamide or 100 microM glibenclamide. The effect of tolbutamide was reversible, while that of glibenclamide was not. In contrast to their activating effect on K+ channels, the K+ channel openers, diazoxide, BRL 38227, and minoxidil sulfate inhibited CFTR Cl- currents. Half-maximal inhibition was observed at approximately 250 microM diazoxide, 50 microM BRL 38227, and 40 microM minoxidil sulfate. The rank order of potency for inhibition of CFTR Cl- currents was: glibenclamide < BRL 38227 approximately equal to minoxidil sulfate > tolbutamide > diazoxide. Site-directed mutations of CFTR in the first membrane-spanning domain and second nucleotide-binding domain did not affect glibenclamide inhibition of CFTR Cl- currents. However, when part of the R domain was deleted, glibenclamide inhibition showed significant voltage dependence. These agents, especially glibenclamide, which was the most potent, may be of value in identifying CFTR Cl- channels. They or related analogues might also prove to be of value in treating diseases such as diarrhea, which may involve increased activity of the CFTR Cl- channel.

ROLE OF ACTION POTENTIAL SHORTENING IN THE PREVENTION OF ARRHYTHMIAS IN CANINE CARDIAC TISSUE

1999 ◽  
Vol 26 (12) ◽  
pp. 964-969 ◽  
Author(s):  
Kawonia P Mull ◽  
Qadriyyah Debnam ◽  
Syeda M Kabir ◽  
Mohit Lal Bhattacharyya
Keyword(s):  
Action Potential ◽  
Cardiac Tissue ◽  
Action Potential Shortening

Modulation of K channels by coexpressed human alpha1C-adrenoceptor in Xenopus oocytes

1997 ◽  
Vol 272 (3) ◽  
pp. H1275-H1286
Author(s):  
G. N. Tseng ◽  
J. A. Yao ◽  
J. Tseng-Crank
Keyword(s):  
Protein Kinase ◽  
Model System ◽  
K Channel ◽  
K Channels ◽  
Channel Modulation ◽  
Channel Function ◽  
Adrenergic Modulation ◽  
Intracellular Ca ◽  
Dependent Protein ◽  
Multiple Receptor

alpha1-Adrenoceptors participate in the regulation of inotropy and chronotropy in the heart. Modulation of cardiac K-channel function plays an important role in these alpha1-adrenergic functions. Studies of the mechanisms of K-channel modulation by alpha1-adrenoceptors are hampered by the coexistence of multiple receptor and channel subtypes in the heart. We therefore used a model system of coexpressing a specific receptor (human alpha1c-adrenoceptor) and a K-channel clone (hIsK, rKv1.2, or rKv1.4) in oocytes. alpha1c-Adrenoceptor stimulation caused a rapid upregulation of hIsK by elevating the intracellular Ca concentration. At least part of this effect was due to an activation of calmodulin and Ca/calmodulin-dependent protein kinase II. On the other hand, alpha1c-adrenoceptor stimulation caused a slow downregulation of rKv1.2 and rKvl.4 by activating protein kinase C. The differential modulation of K channels by alpha1c-adrenoceptors demonstrated in our experiments corroborates the complexity of alpha1-adrenergic functions in the heart. Our results indicate that the oocyte model system can be a useful approach in studying alpha1-adrenergic modulation of ion-channel function and signal transduction.

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