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Published byPrimrose Campbell Modified over 9 years ago
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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 State: Voltage Control
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The “Parts” of a cellular “switch: In VitroIn Numero Cell Membrane + Channel Membrane Capacitance Gated Ion Channel R channel CmCm
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The Action Potential Voltage Activation of Na and K Channels Membrane Potential
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Altering Cellular Stability: Modulating 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 timing The Vulnerable Period stimulus No Response Full Response Partial Response
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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 Current: Evidence of nonlinear resistance Closed Open 2 open Single Cell I
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-60 -50 -40 -30 Observing the Nonlinearity Response of the Na Channel Prob(opening) depends on Vm -120 mV -60 -40 -30 -50
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Destabilizing Wave Motion Stable Rotation Unstable Rotation
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Diffusion via Gap Junction Coupling K+K+
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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
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Single Channel Currents
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