State dependent drug binding to sodium channels in the dentate gyrus (Thomas & Petrou 2013)

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Accession:149174
A Markov model of sodium channels was developed that includes drug binding to fast inactivated states. This was incorporated into a model of the dentate gyrus to investigate the effects of anti-epileptic drugs on neuron and network properties.
Reference:
1 . Thomas EA, Petrou S (2013) Network-specific mechanisms may explain the paradoxical effects of carbamazepine and phenytoin. Epilepsia 54:1195-202 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Realistic Network; Neuron or other electrically excitable cell; Axon; Channel/Receptor;
Brain Region(s)/Organism:
Cell Type(s): Dentate gyrus granule cell; Dentate gyrus mossy cell; Dentate gyrus basket cell; Dentate gyrus hilar cell;
Channel(s): I Na,t; I A; I_AHP;
Gap Junctions:
Receptor(s): GabaA; AMPA;
Gene(s):
Transmitter(s): Gaba; Glutamate;
Simulation Environment: NEURON; MATLAB;
Model Concept(s): Ion Channel Kinetics; Epilepsy; Calcium dynamics; Drug binding; Markov-type model;
Implementer(s): Thomas, Evan [evan at evan-thomas.net];
Search NeuronDB for information about:  Dentate gyrus granule cell; GabaA; AMPA; I Na,t; I A; I_AHP; Gaba; Glutamate;
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ThomasPetrou2013
Fig 4
Data
bgka.mod *
CaBK.mod *
ccanl.mod *
Gfluct2.mod *
gskch.mod *
hyperde3.mod *
ichan2.mod
LcaMig.mod *
nad.mod
nca.mod *
tca.mod *
apchew.m
async.hoc
runall.py
                            
TITLE nad.mod  
 
COMMENT
EAT 14Sep09 Kinetic model based on the Santhakumar et al 2005 sodium channel
            that also allows binding to inactivated states.
ENDCOMMENT
 
UNITS {
    (mA) =(milliamp)
    (mV) =(millivolt)
    (uF) = (microfarad)
	(molar) = (1/liter)
	(nA) = (nanoamp)
	(mM) = (millimolar)
	(um) = (micron)
	FARADAY = 96520 (coul)
	R = 8.3134	(joule/degC)
}
 
? interface 
NEURON { 
SUFFIX nad 
USEION nat READ enat WRITE inat VALENCE 1
RANGE gnat
RANGE gnatbar
RANGE inat
RANGE alphaD, betaD
}
 
INDEPENDENT {t FROM 0 TO 100 WITH 100 (ms)}
 
PARAMETER {
    v (mV) 
    celsius = 6.3 (degC)
    dt (ms) 
    enat  (mV)
	gnatbar (mho/cm2)
    alphaD (/ms)
    betaD (/ms)
}
 
STATE {
O C1 C2 C3 I I1 I2 I3 ID I1D I2D I3D
}
 
KINETIC scheme1 {
rates(v)

~ O  <-> C1  (3*betam, 1*alpham)
~ O  <-> I   (1*betah, 1*alphah)
~ C1 <-> C2  (2*betam, 2*alpham)
~ C2 <-> C3  (1*betam, 3*alpham)
~ I  <-> I1  (3*betam, 1*alpham)
~ I1 <-> I2  (2*betam, 2*alpham)
~ I2 <-> I3  (1*betam, 3*alpham)
~ C1 <-> I1  (1*betah, 1*alphah)
~ C2 <-> I2  (1*betah, 1*alphah)
~ C3 <-> I3  (1*betah, 1*alphah)
~ I  <-> ID  (betaD,   alphaD)
~ I1 <-> I1D (betaD,   alphaD)
~ I2 <-> I2D (betaD,   alphaD)
~ I3 <-> I3D (betaD,   alphaD)

CONSERVE O+C1+C2+C3+I+I1+I2+I3+ID+I1D+I2D+I3D = 1
}


ASSIGNED {
        gnat (mho/cm2) 
        inat (mA/cm2)
        alpham (/ms)
        alphah (/ms)
        betam (/ms)
        betah (/ms)
} 

? currents
BREAKPOINT {
	SOLVE scheme1 METHOD sparse
        gnat = gnatbar*O  
        inat = gnat*(v - enat)
}
 
UNITSOFF
 
INITIAL {
	rates(v)
	SOLVE scheme1 STEADYSTATE sparse
}

LOCAL q10

? rates
PROCEDURE rates(v) {  :Computes rate and other constants at current v.
                      :Call once from HOC to initialize inf at resting v.
       q10 = 3^((celsius - 6.3)/10)
                :"m" sodium activation system - act and inact cross at -40
	alpham = -0.3*vtrap((v+60-17),-5)
	betam = 0.3*vtrap((v+60-45),5)
                :"h" sodium inactivation system
	alphah = 0.23/exp((v+60+5)/20)
	betah = 3.33/(1+exp((v+60-47.5)/-10))
}
 
FUNCTION vtrap(x,y) {  :Traps for 0 in denominator of rate eqns.
        if (fabs(x/y) < 1e-6) {
                vtrap = y*(1 - x/y/2)
        }else{  
                vtrap = x/(exp(x/y) - 1)
        }
}
 
UNITSON


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