What Happens When Mutant Na Channels Lose Their

Function?

C. Frank Starmer

Medical University of South Carolina

Charleston, SC USA

Cell Membrane and a Na Channel

Mutant Sequences

Control of Channel State:Voltage Control

The “Parts” of a cellular “switch:In Vitro In Numero

Cell Membrane + Channel

Membrane Capacitance

Gated Ion Channel

Rchannel

Cm

The Action PotentialVoltage Activation of Na and K Channels

Mem

brane P

otential

Altering Cellular Stability:Modulating Net Current (Inward - Outward)

Action Potentials and ECGs associated with normal and mutant

channels

ECG of a possibly fatal cardiac arrhythmia

How to Initiate a Reentrant Arrhythmia

Supra-threshold excitation impulse

Local asymmetric excitability Established by prior passage of an excitation

wave Anisotropic connectivity

The role of stimulus timingThe Vulnerable Period

stimulus stimulus

stimulus

No Response Full Response

Partial Response

A Mechanism for Cardiac Vulnerability

Vulnerable Period: Normal and Mutant Channels

Properties: cellular and muticellular

Vulnerability in 2D

Decaying(no front)

Spiral(fragment)

Expanding(continuous front)

Summary

Single site mutations alter Na channel function

Altered function alters the transition rates between channel states

From arrays of coupled cells emerges a new property: vulnerability

Excitation within the VP triggers potentially fatal cardiac arrhythmias

Misc backup slides

Single Channel Na Current:Evidence of nonlinear resistance

ClosedOpen2 open

Single Cell

I

-60

-50

-40

-30

kVmVeVpm

/)(1

1)(

)()( 3

NaNaVVhmgVI

Observing the Nonlinearity Response of

the Na Channel

Prob(opening) depends on Vm

-120 mV-60

-40-30

-50

Destabilizing Wave Motion

Stable Rotation Unstable Rotation

Diffusion via Gap Junction Coupling

K+

Splitting of the front into antegrade and retrograde waves:s1-s2 delay controls tearing the antegrade wave from the excited region

s1-s2 = 2.25 s1-s2 = 2.28 s1-s2 = 2.33 s1-s2 = 2.35

Front Bifurcation at the VP Boundary(Bountis Instability)

No Splitting Front + back

splittingFront + back

splitting

Front propagatesBack collapses

Single Channel Currents