Zonisamide-induced inhibition of the firing of APs in hippocampal neurons (Huang et al. 2007)

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Accession:84606
Zonisamide (ZNS), a synthetic benzisoxazole derivative, has been used as an alternative choice in the treatment of epilepsy with a better efficacy and safety profile. However, little is known regarding the mechanism of ZNS actions on ion currents in neurons. We thus investigated its effect on ion currents in differentiated hippocampal 19-7 cells. The ZNS (30 uM) reversibly increased the amplitude of K+ outward currents and paxilline (1 uM) was effective in suppressing ZNS-induced increase of K+ outward currents. In inside-out configuration, ZNS (30 uM) applied to the intracellular face of the membrane did not alter single-channel conductance; however, it did enhance the activity of large-conductance Ca2+-activated K+ (BKCa) channels primarily by decreasing mean closed time. The EC50 value for ZNS-stimulated BKCa channels was 34 uM. This drug caused a left shift in the activation curve of BKCa channels with no change in the gating charge of these channels. ZNS at a concentration greater than 100 uM also reduced the amplitude of A-type K+ current in these cells. A simulation modeling based on hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was also analyzed to investigate the inhibitory effect of ZNS on the firing of simulated action potentials. Taken together, this study suggests that in hippocampal neurons, during the exposure to ZNS, the ZNS-mediated effects on BKCa channels and IA could be one of the ionic mechanisms through which it affects neuronal excitability.
Reference:
1 . Huang CW, Huang CC, Wu SN (2007) Activation by zonisamide, a newer antiepileptic drug, of large-conductance calcium-activated potassium channel in differentiated hippocampal neuron-derived H19-7 cells. J Pharmacol Exp Ther 321:98-106 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell;
Brain Region(s)/Organism:
Cell Type(s): Hippocampus CA3 pyramidal GLU cell;
Channel(s): I K,Ca; I Sodium;
Gap Junctions:
Receptor(s):
Gene(s):
Transmitter(s):
Simulation Environment: XPP;
Model Concept(s): Ion Channel Kinetics; Axonal Action Potentials; Epilepsy;
Implementer(s): Wu, Sheng-Nan [snwu at mail.ncku.edu.tw]; Huang, Chin-Wei;
Search NeuronDB for information about:  Hippocampus CA3 pyramidal GLU cell; I K,Ca; I Sodium;
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Neuron_ZNS
readme.html
Neuron_ZNS.ode
ZNS_BK.pdf
ZNS_graph.JPG
                            
# Adoped from Pinsky-Rinzel CA3 pyramidal cell model
# Pinsky and Rinzel, J Comput Neurosci 1994;1:39-60.
# K(ATP) channel was inserted into the model.
# Parameters for K(ATP) channels are from Koyto model
# Matsuoka et al. Prog Biophys Mol Biol 2004;85:279-299.
# Simulation results were mimicked by the data from H19-7 cells.
# Simulation of zonisamide (ZNS) effect on CA3 pyramidal cells
# Implemented by Drs. Sheng-Nan Wu and Chin-Wei Huang

# initial conditions
init Vs=-60 Vd=-60

# Parameter values
par ip0=0.75
par gLs=0.1  gLd=0.1  gKdr=15  gCa=1  gKahp=0.8

# Parameter values: simulate ZNS effect final_gNa=17  final_gKCa=40,
par init_gKCa=20  final_gKCa=40
par init_gNa=18  final_gNa=17
par VNa=60  VCa=80  VK=-75  VL=-60  Vsyn=0
par gc=2.1 pp=0.5  Cm=3
par alphac=2 betac=0.1
par tstim=8.0e3 n=500
par gkatp=0.0236*(4^0.24)
par iatp=0.1
par natp=50
gKC=if(t<tstim)then(init_gKCa)else(final_gKCa)
gNa=if(t<tstim)then(init_gNa)else(final_gNa)

# Output cols are t, ODEs, AUXs in order, here:
# t versus vd cad hs ns sd cd qd gqk gkc 
Vs'=(-gLs*(Vs-VL)-gNa*(Minfs(Vs)^2)*hs*(Vs-VNa)-gKdr*ns*(Vs-VK)-gkatp*natp*poatp*(Vs-VK)+(gc/pp)*(Vd-Vs)+Ip0/pp)/Cm
Vd'=(-gLd*(Vd-VL)-ICad-gKahp*qd*(Vd-VK)-gKC*cd*chid*(Vd-VK)-gkatp*natp*poatp*(Vd-VK)+(gc*(Vs-Vd))/(1.0-pp))/Cm
Cad'=  -0.13*ICad-0.075*Cad
hs'=  alphahs(Vs)-(alphahs(Vs)+betahs(Vs))*hs
ns'=  alphans(Vs)-(alphans(Vs)+betans(Vs))*ns
sd'=  alphasd(Vd)-(alphasd(Vd)+betasd(Vd))*sd
cd'=  alphacd(Vd)-(alphacd(Vd)+betacd(Vd))*cd
qd'=  alphaqd-(alphaqd+betaqd)*qd

# Pyramidal cell functions
ICad =  gCa*sd*sd*(Vd-VCa)
alphams(v) =  0.32*(-46.9-v)/(exp((-46.9-v)/4.0)-1.0)
betams(v) =  0.28*(v+19.9)/(exp((v+19.9)/5.0)-1.0)
Minfs(v) =  alphams(v)/(alphams(v)+betams(v))
alphans(v) =  0.016*(-24.9-v)/(exp((-24.9-v)/5.0)-1.0)
betans(v) =  0.25*exp(-1.0-0.025*v)
alphahs(v) =  0.128*exp((-43.0-v)/18.0)
betahs(v) =  4.0/(1.0+exp((-20.0-v)/5.0))
alphasd(v) = 1.6/(1.0+exp(-0.072*(v-5.0)))
betasd(v) =  0.02*(v+8.9)/(exp((v+8.9)/5.0)-1.0)
alphacd(v) = (1.0-heav(v+10.0))*exp((v+50.0)/11-(v+53.5)/27)/18.975+heav(v+10.0)*2.0*exp((-53.5-v)/27.0)
betacd(v) =  (1.0-heav(v+10.0))*(2.0*exp((-53.5-v)/27.0)-alphacd(v))
alphaqd = min(0.00002*Cad,0.01)
betaqd = 0.001
chid = min(Cad/250.0,1.0)

# Level of intracellular ATP concentration
poatp = 0.8/(1+(iatp/0.023)^2)

# auxiliary equationns
aux Ica=ICad
aux gkq = gKahp*qd
aux ikca = gKC*cd*chid*(Vd-VK)
aux ina = gNa*(Minfs(Vs)^2)*hs*(Vs-VNa)
aux ikatp = gkatp*natp*poatp*(Vs-VK)

# integrator params
@ maxstor=1600000,total=2.0e4,bound=10000,xlo=0,xhi=2.0e4,ylo=-90,yhi=40
@ meth=cvode,atol=0.0001,toler=0.0001,dt=0.05

done

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