Influence of ionic current on Na+ channel gating in crayfish giant axon

Nature ◽  
1982 ◽  
Vol 296 (5856) ◽  
pp. 450-452
Author(s):  
Peter Shrager ◽  
Mei-Ven C. Lo
Keyword(s):  
Channel Gating ◽  
Ionic Current ◽  
Giant Axon ◽  
Na Channel

scholarly journals Molecular Action of Lidocaine on the Voltage Sensors of Sodium Channels

2003 ◽  
Vol 121 (2) ◽  
pp. 163-175 ◽  
Author(s):  
Michael F. Sheets ◽  
Dorothy A. Hanck
Keyword(s):  
Channel Gating ◽  
Ionic Current ◽  
Na Channel ◽  
Relative Reduction ◽  
Charge Movement ◽  
Charge Voltage ◽  
Voltage Sensors ◽  
Gating Charge ◽  
Voltage Dependent ◽  
Domain Iii

Block of sodium ionic current by lidocaine is associated with alteration of the gating charge-voltage (Q-V) relationship characterized by a 38% reduction in maximal gating charge (Qmax) and by the appearance of additional gating charge at negative test potentials. We investigated the molecular basis of the lidocaine-induced reduction in cardiac Na channel–gating charge by sequentially neutralizing basic residues in each of the voltage sensors (S4 segments) in the four domains of the human heart Na channel (hH1a). By determining the relative reduction in the Qmax of each mutant channel modified by lidocaine we identified those S4 segments that contributed to a reduction in gating charge. No interaction of lidocaine was found with the voltage sensors in domains I or II. The largest inhibition of charge movement was found for the S4 of domain III consistent with lidocaine completely inhibiting its movement. Protection experiments with intracellular MTSET (a charged sulfhydryl reagent) in a Na channel with the fourth outermost arginine in the S4 of domain III mutated to a cysteine demonstrated that lidocaine stabilized the S4 in domain III in a depolarized configuration. Lidocaine also partially inhibited movement of the S4 in domain IV, but lidocaine's most dramatic effect was to alter the voltage-dependent charge movement of the S4 in domain IV such that it accounted for the appearance of additional gating charge at potentials near −100 mV. These findings suggest that lidocaine's actions on Na channel gating charge result from allosteric coupling of the binding site(s) of lidocaine to the voltage sensors formed by the S4 segments in domains III and IV.

scholarly journals An Inactivation Stabilizer of the Na+ Channel Acts as an Opportunistic Pore Blocker Modulated by External Na+

2005 ◽  
Vol 125 (5) ◽  
pp. 465-481 ◽  
Author(s):  
Ya-Chin Yang ◽  
Chung-Chin Kuo
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Dissociation Constants ◽  
Channel Gating ◽  
Structural Motif ◽  
Na Channel ◽  
Channel Pore ◽  
Conduction Pathway ◽  
Gating Process ◽  
Pore Blocker

The Na+ channel is the primary target of anticonvulsants carbamazepine, phenytoin, and lamotrigine. These drugs modify Na+ channel gating as they have much higher binding affinity to the inactivated state than to the resting state of the channel. It has been proposed that these drugs bind to the Na+ channel pore with a common diphenyl structural motif. Diclofenac is a widely prescribed anti-inflammatory agent that has a similar diphenyl motif in its structure. In this study, we found that diclofenac modifies Na+ channel gating in a way similar to the foregoing anticonvulsants. The dissociation constants of diclofenac binding to the resting, activated, and inactivated Na+ channels are ∼880 μM, ∼88 μM, and ∼7 μM, respectively. The changing affinity well depicts the gradual shaping of a use-dependent receptor along the gating process. Most interestingly, diclofenac does not show the pore-blocking effect of carbamazepine on the Na+ channel when the external solution contains 150 mM Na+, but is turned into an effective Na+ channel pore blocker if the extracellular solution contains no Na+. In contrast, internal Na+ has only negligible effect on the functional consequences of diclofenac binding. Diclofenac thus acts as an “opportunistic” pore blocker modulated by external but not internal Na+, indicating that the diclofenac binding site is located at the junction of a widened part and an acutely narrowed part of the ion conduction pathway, and faces the extracellular rather than the intracellular solution. The diclofenac binding site thus is most likely located at the external pore mouth, and undergoes delicate conformational changes modulated by external Na+ along the gating process of the Na+ channel.

Abstract 17272: Ionic Current Remodeling Delays the Electrical Recovery of the Senescent Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sergio Signore ◽  
Giulia Borghetti ◽  
Ramaswamy Kannappan ◽  
Andrea Sorrentino ◽  
Antonio Cannata ◽  
...  
Keyword(s):  
Qt Interval ◽  
Ventricular Arrhythmias ◽  
Ionic Current ◽  
Monophasic Action Potential ◽  
K Channel ◽  
Delayed Rectifier ◽  
Inactivation Kinetics ◽  
Na Channel ◽  
Surface Ecg ◽  
Gene And Protein Expression

Cardiac aging is associated with lengthening of the QT interval, a condition that enhances malignant ventricular arrhythmias and sudden death. The aim of this study was to establish whether ionic currents are altered in old myocytes contributing to the protracted electrical recovery of the senescent heart. Thus, mice at 3-30 months of age were studied by ECG and patch-clamp; these physiological determinations were complemented with molecular assays for the analysis of ion channel proteins. By surface ECG and telemetry system, PR, QRS and QT intervals were prolonged in mice at 25 months or older. These delays were maintained in ex-vivo Langendorff preparations. In comparison to young, epicardial monophasic action potential (AP) duration at 50% and 90% repolarization were 1.6- and 1.2-fold larger in old LV, respectively. Moreover, senescent hearts presented a 60% higher incidence of arrhythmias. In isolated myocytes, prolongation of the early (+47%), intermediate (+117%) and late (+75%) repolarization phases of the AP were identified in cells from old animals, whereas resting membrane potential, upstroke amplitude and +dV/dt were preserved. Voltage-clamp experiments were then performed to measure ionic current properties. The rapidly activating K+ current, which consists of the transient outward and ultrarapid delayed rectifier (Ito+Kur), is responsible for the early repolarization of the AP, and was significantly reduced in old myocytes. Molecular studies revealed low levels of transcripts and proteins for K+ channel subunits Kv1.4, Kv1.5 and KChiP2 in senescent cells. Also, the late Na+ current INaL, which presents slow inactivation kinetics and is operative during AP repolarization, was 1.5-fold larger in old cells. These changes were associated with alterations in gene and protein expression of Na+ channel subunits. Inhibition of INaL with mexiletine significantly shortened the intermediate and late repolarization phases of the AP in both myocytes and perfused myocardium from old mice. Importantly, INaL inhibition in vivo shortened the QT interval of senescent mice by 12%. Thus, defects in ionic current occur with aging resulting in prolongation of the AP and delays in electrical recovery which may lead to malignant ventricular arrhythmias.

scholarly journals Water molecules in a pore during Na channel gating.

1999 ◽  
Vol 39 (supplement) ◽  
pp. S59
Author(s):  
F. Kukita
Keyword(s):  
Channel Gating ◽  
Na Channel ◽  
Water Molecules

scholarly journals Calcium ion as a cofactor in Na channel gating.

1991 ◽  
Vol 88 (15) ◽  
pp. 6528-6531 ◽  
Author(s):  
C. M. Armstrong ◽  
G. Cota
Keyword(s):  
Calcium Ion ◽  
Channel Gating ◽  
Na Channel

Temperature and impulse velocity in giant axon of squid Loligo pealei

1975 ◽  
Vol 229 (5) ◽  
pp. 1249-1253 ◽  
Author(s):  
DM Easton ◽  
CE Swenberg
Keyword(s):  
Experimental Data ◽  
Fourth Order ◽  
Ionic Current ◽  
Membrane Conductance ◽  
Giant Axon ◽  
Velocity Versus ◽  
Stability Function ◽  
The Difference ◽  
Q10 Values ◽  
Loligo Pealei

Impulse propagation velocity as a function of temperature in the range 5--20degreesC was obtained by external recording from the giant axon of Loligo pealei. The stellar nerve was set into a chamber allowing continuous superfusion, temperature control, and double recording of the impulse. Velocity was calculated from the interval between the spike peaks. The Q10 of velocity was about 1.8. At all temperatures, the velocity increased with time so that only data obtained during the 1st h or 2 could be generally considered to be comparable. Impulse block occurred below --3.4degreesC, in contrast to the giant axon of L. vulgaris, which blocks at about 0degreeC, but at the higher range of temperatures, the velocity in the L. pealei axons was not as well sustained as in those of L. vulgaris. The expected impulse velocity was calculated from Huxley's stability function f(beta) by approximating that function to a fourth-order polynominal and by substituting into it suitable ratios of available Q10 values relating to membrane conductance, ionic current, capacitance, and axoplasmic resistance. The calculation provided an improved fit to published experimental data on L. vulgaris. The difference in slope of the log velocity versus temperature plots, between the presumably warm acclimatized L. vulgaris and the cold-acclimatized L. pealei, was present in both experimental and calculated curves.

Sign in / Sign up

Export Citation Format

Share Document