1. What Happens When Mutant Na Channels Lose Their Function? C. Frank Starmer Medical University of South Carolina Charleston, SC USA

2. Cell Membrane and a Na Channel

3. Mutant Sequences

4. Control of Channel State: Voltage Control

5. The “Parts” of a cellular “switch: In VitroIn Numero Cell Membrane + Channel Membrane Capacitance Gated Ion Channel R channel CmCm

6. The Action Potential Voltage Activation of Na and K Channels Membrane Potential

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

8. Action Potentials and ECGs associated with normal and mutant channels

9. ECG of a possibly fatal cardiac arrhythmia

10. How to Initiate a Reentrant Arrhythmia Supra-threshold excitation impulse Local asymmetric excitability Established by prior passage of an excitation wave Anisotropic connectivity

11. The role of stimulus timing The Vulnerable Period stimulus No Response Full Response Partial Response

12. A Mechanism for Cardiac Vulnerability

13. Vulnerable Period: Normal and Mutant Channels

14. Properties: cellular and muticellular

15. Vulnerability in 2D Decaying (no front) Spiral (fragment) Expanding (continuous front)

16. 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

17. Misc backup slides

18. Single Channel Na Current: Evidence of nonlinear resistance Closed Open 2 open Single Cell I

19. -60 -50 -40 -30 Observing the Nonlinearity Response of the Na Channel Prob(opening) depends on Vm -120 mV -60 -40 -30 -50

20. Destabilizing Wave Motion Stable Rotation Unstable Rotation

21. Diffusion via Gap Junction Coupling K+K+

22. Splitting of the front into antegrade and retrograde waves: s1-s2 delay controls tearing the antegrade wave from the excited region s1-s2 = 2.25s1-s2 = 2.28 s1-s2 = 2.33s1-s2 = 2.35 Front Bifurcation at the VP Boundary (Bountis Instability) No Splitting Front + back splitting Front + back splitting Front propagates Back collapses

23. Single Channel Currents