What Happens When Mutant Na Channels Lose Their Function

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What Happens When Mutant Na Channels Lose Their
Function?

• C. Frank Starmer
• Medical University of South Carolina
• Charleston, SC USA

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Cell Membrane and a Na Channel
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Mutant Sequences
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Control of Channel StateVoltage Control
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The Parts of a cellular switchIn Vitro In
Numero
Rchannel
Gated Ion Channel
Cm
Membrane Capacitance
Cell Membrane Channel
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The Action PotentialVoltage Activation of Na and
K Channels
Membrane Potential
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Altering Cellular StabilityModulating Net
Current (Inward - Outward)
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Action Potentials and ECGs associated with normal
and mutant channels
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ECG of a possibly fatal cardiac arrhythmia
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How to Initiate a Reentrant Arrhythmia

• Supra-threshold excitation impulse
• Local asymmetric excitability
• Established by prior passage of an excitation
  wave
• Anisotropic connectivity

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The role of stimulus timingThe Vulnerable Period
Full Response
No Response
Partial Response
stimulus
stimulus
stimulus
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A Mechanism for Cardiac Vulnerability
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Vulnerable Period Normal and Mutant Channels
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Properties cellular and muticellular
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Vulnerability in 2D
Decaying (no front)
Spiral (fragment)
Expanding (continuous front)
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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

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Misc backup slides
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Single Channel Na CurrentEvidence of nonlinear
resistance
2 open
Open
Closed
I
Single Cell
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Observing the Nonlinearity Response of the Na
Channel Prob(opening) depends on Vm
-60
-50
-40
-30
-40
-50
-30
-60
-120 mV
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Destabilizing Wave Motion
Unstable Rotation
Stable Rotation
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Diffusion via Gap Junction Coupling
K
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Front Bifurcation at the VP Boundary (Bountis
Instability)
Splitting of the front into antegrade and
retrograde waves s1-s2 delay controls tearing
the antegrade wave from the excited region
s1-s2 2.33
s1-s2 2.35
s1-s2 2.25
s1-s2 2.28
Front propagates Back collapses
Front back splitting
Front back splitting
No Splitting
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Single Channel Currents