Gating Modeling of Ion Channels Chu-Pin Lo ( 羅主斌 ) Department of Applied Mathematics Providence University 2010/01/12 (Workshop on Dynamics for Coupled Systems, CMMSC)
Outline Cardiac Electrophysiology Modeling Techniques (electrical part) Full Current Flux Form: PNP model Gating Modeling (1). Experiment Measurements for Gating Issues (2). Classical Kinetics (3). Hodgkin-Huxley Theory (cell scale) (4). Markovian Process Method (channel scale) (5). Smoluchowski model (channel scale) Pharmacological Applications
Cardiac Electrophysiology
Electrophysiology of the cardiac muscle cell
ECG & Action Potentials Single Cell Action Potential (Microscopic) ECG (Macroscopic)
Macroscopic property Mesoscopic property
Computing of ECG ( 心電圖 )
Isotropic, space homogeneous of conductive tensor, and infinite media ECG= Where and
Computing of ECG ( 心電圖 ), Cont. Bounded media, piecewise constant and isotropic conductive tensor ECG= boundary element method
Computing of ECG ( 心電圖 ), Cont. Real case (finite media, anisotropic and space heterogeneity conductive tensor) finite difference, finite element, finite volume methods
Cellular Basis of ECG
Modeling Techniques (electrical part)
Modeling Approaches (cell and channel scale) Poisson-Nernst Planck+Density functional Theory (for full open flux) (channel scale) Barrier model (for full open flux) (channel scale) Hodgkin-Huxley Theory (for gating issue)(cell scale) Markovian Process Method (for gating issue)(channel scale) Smoluchowski model (for gating issue)(channel scale)
(sub)channel scale
Current Form: single channel and single cell (1)Single channel current: I_s=(gating factor/open probability) ‧ (full open flux) (2) Single cell current: I_t=(total channels number) ‧ I_s
Tissue scale
Macroscopic property Mesoscopic property
Organ scale
Rat Left Ventricle
Fiber-Sheet Structure
Incorporation of fiber-sheet structure into bidomain Model
Full Current Flux Form: Poisson-Nernst-Planck Model (PNP) & Density Functional Theory (DFT)
PNP model (continuum model) Nernst- Planck equation (derived from molecular Langevin equation) continuity equation
Poisson equation for electrostatic potential
Density Functional Theory (DFT): excess chemical potential description (finite size charged particle)
Simulation Results: flux form
Simulation Result: Permeation Selectivity for Ca2+
Two famous flux form: (1). Goldman-Hodgkin-Katz (GHK) current form Conditions: short channel Or low ionic concentrations of either side of the membrane Or constant field PNP with only ideal electrochemical potential (point particle)
Two famous flux form: (2). Linear I-V relation (Ohm’s law) Conditions: long channel high ionic concentrations of either side of the membrane PNP with only ideal electrochemical potential (point particle)
Gating Modeling Experiment Measurements for Gating Issues Classical Kinetics Hodgkin-Huxley Theory (cell scale) Markovian Process Method (channel scale) Smoluchowski model (channel scale)
Ion Channel Structure
Experiment Measurements for Gating Issues
Fluctuation analysis Single-channel recording Gating current
Fluctuation Analysis
Single Channel Recording
Single channel recording Mean open (shut) time The time to first opening of a channel (first-latency distribution) Number of times that a channel opens before inactivation Conditional probability that an open period of a certain length is followed immediately by a closed period of a certain length Hidden Markov analysis
Complement to classical kinetics (single channel recording) macro current single channel current
Hidden Markov Analysis
Gating Current
Gating Mechanism: gating current (two states transition) Conformational change of channel protein Gating current (charge): energy supply one-step conformational change probability ratio of open to closed states by Boltzmann equation open probability of channel
Bertil Hille, 2001
Gating Mechanism: gating current (multiple states transition)
Gating Mechanism: gating current (multiple states transition):conti Bertil Hille, 2001
Classical Kinetics
Gating Mechanism: Classical kinetics
Gating Issue: Hodgkin-Huxley Model (single cell model)
stimulus current capacitance current Ionic currents
Model Formalism and Experimental Protocol Design
Activation (steady state) protocol: tail current analysis
Inactivation (steady state) protocol
Recovery protocol (1)
Recovery protocol (2) Modeling formula for recovery kinetics
Time course determination: time constant activation deactivation inactivation recovery
Deactivation experimental protocol (used for time constant determination of deactivation phase)
Gating Issue: Markov Model (single channel and cell model, discrete protein state)
Example 1 (Fitzhugh, 1965) (Markovian version of HH model) INa channel IK channel
Example 2 (Vandenberg, Bezanilla, Perozo, 1990,1991)(match the single channel recording and gating current measure) INa channel IK channel
Example 3 INa IK transition rate
Comparison (INa)
Comparison (action potential)
Differences between Examples Activation and inactivation are kinetically independent in example 1 and dependent in example 2,3 Fast activation and slow inactivation in examples 1,2; slow activation and fast inactivation in example 3
Relation between HH & Markov Models
Relation between HH & Markov Models, Conti.
transition rate determination
Gating issue: Smoluchowski Model (Fokker-Planck type model in energy landscape, continuuum protein state)
Probability Flux Calculation (Fokker-Planck Equation) Smoluchowski Model :
Example1
Example 2
Potential of mean field (PMF)
Langevin Equation
Computation of rate constant rate constant = 1/T mfp mean first passage time (mfp)
Computation of Gating Current master equation gating current
Example 3
Potential Calculation Linearized Poisson- Boltzman with transmembrane potential effect
Movie
Pharmacological Applications
Thanks for your Attention !