scholarly journals Reduced Na + and higher K + channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

Open Biology ◽  
2012 ◽  
Vol 2 (6) ◽  
pp. 120072 ◽  
Author(s):  
Claire A. Martin ◽  
Urszula Siedlecka ◽  
Kristin Kemmerich ◽  
Jason Lawrence ◽  
James Cartledge ◽  
...  
Keyword(s):  
Voltage Dependence ◽  
Outward Current ◽  
K Channel ◽  
Transient Outward Current ◽  
Wild Type ◽  
Channel Expression ◽  
Mrna And Protein Expression ◽  
The Right ◽  
And Function ◽  
Electrophysiological Mechanism

Brugada syndrome (BrS) is associated with ventricular tachycardia originating particularly in the right ventricle (RV). We explore electrophysiological features predisposing to such arrhythmic tendency and their possible RV localization in a heterozygotic Scn5a+/− murine model. Na v 1.5 mRNA and protein expression were lower in Scn5a+/− than wild-type (WT), with a further reduction in the RV compared with the left ventricle (LV). RVs showed higher expression levels of K v 4.2, K v 4.3 and KChIP2 in both Scn5a+/− and WT. Action potential upstroke velocity and maximum Na + current ( I Na ) density were correspondingly decreased in Scn5a+/− , with a further reduction in the RV. The voltage dependence of inactivation was shifted to more negative values in Scn5a+/−. These findings are predictive of a localized depolarization abnormality leading to slowed conduction. Persistent Na + current ( I pNa ) density was decreased in a similar pattern to I Na . RV transient outward current ( I to ) density was greater than LV in both WT and Scn5a+/− , and had larger time constants of inactivation. These findings were also consistent with the observation that AP durations were smallest in the RV of Scn5a+/− , fulfilling predictions of an increased heterogeneity of repolarization as an additional possible electrophysiological mechanism for arrhythmogenesis in BrS.

Hodgkin-Huxley and partially coupled inactivation models yield different voltage dependence of block

1997 ◽  
Vol 272 (4) ◽  
pp. H2013-H2022 ◽  
Author(s):  
S. Liu ◽  
R. L. Rasmusson
Keyword(s):  
Voltage Dependence ◽  
Channel Model ◽  
Outward Current ◽  
Blocking Agent ◽  
K Channel ◽  
Transient Outward Current ◽  
Channel Blockers ◽  
Channel Block ◽  
Current Channel ◽  
Voltage Dependent

K+ channel blockers have been shown to exhibit complex time- and voltage-dependent effects on cardiac K+ currents. Whereas much attention has been focused on the state dependence of K+ channel block, how a particular channel model can alter the predicted time and voltage dependence of channel block remains unexplored. In this study, using two different model formalisms for the same cardiac transient outward current channel, we compare the effects of a theoretical open-state specific channel blocker on macroscopic currents. Model 1 is a Hodgkin-Huxley-like model, in which inactivation is an intrinsically voltage-dependent process and occurs independently of activation. Model 2 is a "partially coupled" model, in which inactivation is intrinsically voltage insensitive but requires channel activation before it can proceed. In the absence of drug (blocking agent), the two models reproduce the macroscopic current data. In the presence of blocking agent, the two models can differ substantially, with model 1 displaying much less block than model 2. We also examine simple mathematically convenient modifications to the Hodgkin-Huxley formalism, which reproduce some, but not all, of the use-dependent properties of block. Thus model formalism is important for analysis and simulation of state-specific drug-channel interactions.

I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium

1996 ◽  
Vol 271 (2) ◽  
pp. H548-H561 ◽  
Author(s):  
J. M. Di Diego ◽  
Z. Q. Sun ◽  
C. Antzelevitch
Keyword(s):  
Action Potential ◽  
Phase 1 ◽  
Outward Current ◽  
Disulfonic Acid ◽  
Transient Outward Current ◽  
Pharmacological Agents ◽  
Whole Cell Patch Clamp ◽  
Chloride Channel Blocker ◽  
The Right ◽  
Basic Cycle Length

Transmural heterogeneities of repolarizing currents underlie prominent differences in the electrophysiology and pharmacology of ventricular epicardial, endocardial, and M cells in a number of species. The degree to which heterogeneities exist between the right and left ventricles is not well appreciated. The present study uses standard microelectrode and whole cell patch-clamp techniques to contrast the electrophysiological characteristics and pharmacological responsiveness of tissues and myocytes isolated from right (RVE) and left canine ventricular epicardium (LVE). RVE and LVE studied under nearly identical conditions displayed major differences in the early repolarizing phases of the action potential. The magnitude of phase 1 in RVE was nearly threefold that in LVE: 28.7 +/- 6.2 vs. 10.6 +/- 4.1 mV (basic cycle length = 2,000 ms). Phase 1 in RVE was also more sensitive to alterations of the stimulation rate and to 4-aminopyridine (4-AP), suggesting a much greater contribution of the transient outward current (I(to) 1) in RVE than in LVE. The combination of 4-AP plus ryanodine, low chloride, or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (chloride channel blocker) completely eliminated the notch and all rate dependence of the early phases of the action potential, making RVE and LVE indistinguishable. At +70 mV, RVE myocytes displayed peak I(to) 1 densities between 28 and 37 pA/pF. LVE myocytes included cells with similar I(to) 1 densities (thought to represent subsurface cells) but also cells with much smaller current levels (thought to represent surface cells). Average peak I(to) 1 density was significantly smaller in LVE than in RVE at voltages more than or equal to +10 mV. Our data point to prominent differences in the magnitude of the I(to) 1-mediated action potential notch in cells at the surface of RVE compared with the LVE and suggest that important distinctions may exist in the response of these two tissues to pharmacological agents and pathophysiological states, as previously demonstrated for epicardium and endocardium. Our findings also suggest that a calcium-activated outward current contributes to the early repolarization phase in RVE and LVE and that the influence of this current, although small, is more important in the left ventricle.

scholarly journals The Structure and Function of the DNA from Bacteriophage Lambda

1966 ◽  
Vol 49 (6) ◽  
pp. 29-57 ◽  
Author(s):  
David S. Hogness
Keyword(s):  
Early Gene ◽  
Second Step ◽  
Wild Type ◽  
Gene Orientation ◽  
Variant Gene ◽  
Position And Orientation ◽  
The Right ◽  
And Function ◽  
Lambda Dna

The position and orientation of genes in lambda and lambda dg DNA are described. The position of six genes located in the right half of isolated lambda DNA was found to be -(N, iλ)--O-P---Q-R-(right end of DNA), which is their order on the genetic map of the vegetative phage. The order of the three genes of the galactose operon (k, t, and e) located in the left half of lambda dg DNA was found to be (left end of DNA)----k-t-e-, consistent with Campbell's model (5) for the formation of this variant. Gene orientation, defined as the direction of transcription along the DNA, is inferred to be from right to left for the galactose operon in lambda dg DNA. The strand of lambda DNA which functions as template in transcription of N, an "early" gene required for normal replication of lambda DNA, was determined as a first step in ascertaining the orientation of this gene. The method includes isolation of each strand, formation of each of two heteroduplex molecules consisting of one strand from wild-type and one from an N mutant) and comparison of their N activities. The second step, which consists of ascertaining the 5'-to-3' direction of each strand, is discussed, as is a determination of the orientation of gene R.

scholarly journals Properties of "creep currents" in single frog atrial cells.

1986 ◽  
Vol 87 (6) ◽  
pp. 833-855 ◽  
Author(s):  
J R Hume ◽  
A Uehara
Keyword(s):  
Time Course ◽  
Outward Current ◽  
Membrane Current ◽  
K Channel ◽  
Transient Outward Current ◽  
Ca Channel ◽  
Purkinje Fibers ◽  
Atrial Cells ◽  
Cardiac Purkinje Fibers ◽  
Inward Currents

Changes in membrane current in response to an elevation of [Na]i were studied in enzymatically dispersed frog atrial cells. Na loading by either intracellular dialysis or exposure to the Na ionophore monensin produces changes in membrane current that resemble the "creep currents" originally observed in cardiac Purkinje fibers during exposure to low-K solutions. Na loading induces a transient outward current during depolarizing voltage-clamp pulses, followed by an inward current in response to repolarization back to the holding potential. In contrast to cardiac Purkinje fibers, Na loading of frog atrial cells induces creep currents without accompanying transient inward currents. Creep currents induced by Na loading are insensitive to K channel antagonists like Cs and 4-aminopyridine; they are not influenced by doses of Ca channel antagonists that abolish iCa, but are sensitive to changes in [Ca]o or [Na]o. A comparison of the time course of development of inward creep currents are not tail currents associated with iCa. Inward creep currents can also be induced by experimental interventions that increase the iCa amplitude. Exposure to isoproterenol enhances the iCa amplitude and induces inward creep currents; both can be attenuated by Ca channel antagonists. Both inward and outward creep currents are blocked by low doses of La, independently of La's ability to block iCa. It is concluded that (a) creep currents are not mediated by voltage-gated Na, Ca, or K channels or by an electrogenic Na,K pump; (b) inward creep currents induced either by Na loading or in response to an increase in the amplitude of iCa are triggered by an elevation of [Ca]i; and (c) creep currents may be generated by either an electrogenic Na/Ca exchange mechanism or by a nonselective cation channel activated by [Ca]i.

Divalent cations modulate the transient outward current in rat ventricular myocytes

1991 ◽  
Vol 261 (2) ◽  
pp. C310-C318 ◽  
Author(s):  
Z. S. Agus ◽  
I. D. Dukes ◽  
M. Morad
Keyword(s):  
Hippocampal Neurons ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Divalent Cations ◽  
Outward Current ◽  
Transient Outward Current ◽  
Patch Clamp Technique ◽  
Rat Ventricular Myocytes ◽  
Specific Effects ◽  
Whole Cell Patch Clamp

The modulation of the transient outward K+ current (Ito) by divalent cations was studied in enzymatically isolated rat ventricular myocytes with the whole cell patch-clamp technique. At holding potentials negative to -70 mV, 1 mM Cd2+ suppressed Ito, whereas, at potentials positive to -50 mV, the current was augmented. These effects were caused by shifts in the voltage dependence of both activation and inactivation of Ito toward more positive potentials. Cd2+ also slowed the activation kinetics of Ito by shifting the voltage dependence of its rate of activation, but the rate of inactivation was unaffected. Other divalent cations produced similar shifts but at markedly different concentrations. Thus, in the millimolar range, a rightward shift of approximately 20 mV was produced by 3 Co2+, 5 Ni2+, and 10 Ca2+, whereas 10 microM concentrations of Cu2+ and Zn2+ produced equivalent shifts. Similar effects were seen in hippocampal neurons with micromolar concentrations of Zn2+. Thus divalent cations have marked and specific effects on the kinetics and voltage dependence of Ito and may serve as a regulatory mechanism in its activation, particularly in cells with resting potentials positive to -60 mV.

scholarly journals KCa3.1 K+ Channel Expression and Function in Human Bronchial Epithelial Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0145259 ◽  
Author(s):  
Greer K. Arthur ◽  
S. Mark Duffy ◽  
Katy M. Roach ◽  
Rob A. Hirst ◽  
Aarti Shikotra ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
K Channel ◽  
Human Bronchial Epithelial Cells ◽  
Bronchial Epithelial ◽  
Channel Expression ◽  
And Function

Sustained outward current observed after I(to1) inactivation in rabbit atrial myocytes is a novel Cl- current

1992 ◽  
Vol 263 (6) ◽  
pp. H1967-H1971 ◽  
Author(s):  
D. Y. Duan ◽  
B. Fermini ◽  
S. Nattel
Keyword(s):  
Reversal Potential ◽  
Outward Current ◽  
Cell Voltage ◽  
Cell Swelling ◽  
Disulfonic Acid ◽  
K Channel ◽  
Transient Outward Current ◽  
Channel Blockers ◽  
Atrial Myocytes ◽  
K Concentration

In rabbit atrial myocytes, depolarization of the membrane results in a rapidly activating transient outward current (I(to)) that then decays to a sustained level. The sustained current (Isus) remains constant for at least 5 s during continued depolarization. The present study was designed to identify the ionic mechanism underlying Isus with the use of whole cell voltage-clamp techniques. After exposure to 2 mM 4-aminopyridine (4-AP), the 4-AP-sensitive transient outward current (I(to1)) was abolished, but Isus was unaffected. Isus was not blocked by the K+ channel blockers tetraethylammonium chloride and Ba2+, was not changed by increasing superfusate K+ concentration, and was still present when K+ was replaced by Cs+ in both the superfusate and the pipette. Isus was significantly reduced by the Cl- transport blockers 4-acetamido-4'-isothiocyanatostilbene-2.2'-disulfonic acid and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. The current-voltage relations of Isus showed outward rectification, and the reversal potential of Isus shifted with changes in the transmembrane Cl- gradient in the fashion expected for a Cl- current. We conclude that Isus in rabbit atrium is due to a noninactivating Cl- current which, unlike previously described cardiac Cl- currents, is manifest in the absence of exogenous stimulators of adenosine 3',5'-cyclic monophosphate formation, cytosolic Ca2+ transients, or cell swelling.

Sign in / Sign up

Export Citation Format

Share Document