What Happens When Mutant Na Channels Lose Their
Function?
C. Frank Starmer
Medical University of South Carolina
Charleston, SC USA
The “Parts” of a cellular “switch:In Vitro In Numero
Cell Membrane + Channel
Membrane Capacitance
Gated Ion Channel
Rchannel
Cm
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
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
-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
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