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Sodium Channel Structure, Function, Gating and Involvement in Disease. David R. Marks, M.Sc. . An Overview. Sodium Channel Structure - Current theory and Types of Na+ Channels Sodium Channel Function Current theory of inactivation Modulation Pharmacology Activation. An Overview Cont’d.
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David R. Marks, M.Sc.
- Current theory and Types of Na+ Channels
Cartoon representation of the “typical” voltage-activated sodium channel
-A resting state when it can respond to a depolarizing voltage changes
-Activated, when it allows flow of Na+ ions through the
-Inactivated, when subjected to a “suprathreshold” potential, the channel will not open
that the inactivation gate
“swings” shut, turning off
1. Kv1.3 cDNA in Plasmid
2. Lipofectamine complexing
3. Add to Dishes
4. Patch 28-48 hrs after
In the S6 domain
Proposed conformational shift of A-helix caused by substitution of Proline for G219
Prolines in alpha helices after the first turn (4th residue) cause a kink in the helix.
This kink is caused by proline being unable to complete the
H-bonding chain of the helix and steric or rotamer effects that keep proline from
adapting the prefered helical geometry
negative voltages) than the wild-type
V ½ : Voltage at which ½ of channels present are in the open state
Comparable to Km in that it is a measure of the ability of a channel to activate
Do not exert as significant effects in the
activation (V ½)
Influence of hybrid Na+ channel subunits on gating and biophysical properties
course. This is believed to be the result of the expression of two distinct isoforms
of voltage-gated Na+ channels
NaV 1.2/1.6 are expressed over
long distances (> 10μm)
B-amyloid are pepties associated with neurodegenerative diseases, and can accumulate
in fibrillar aggregates
NaV1.6 yields an
Increase in Na/Ca
to harmful levels
Sensitive to TTX, but resistant to
TTX eliminates lidocaine-insensitive current
Other than traumatic cardiac arrest,
arrhythmias degenerate into ventricular
fibrillation or ventricular tachycardias.
“circus movement” whereby tissue
The purpose of defibrillation of ventricular arrhythmias is to apply a controlled electrical
shock to the heart, which leads to depolarization of the entire electrical conduction
system of the heart. When the heart repolarizes, the normal electrical conduction
may restore itself
Depolarization theoretically inactivates all voltage-gated Na+ channels, and allows
Voltage-gated potassium channels to activate, and help hyperpolarize the membrane
After phosphorylation/ phosphate cleavage