May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a...
-
Upload
horatio-bond -
Category
Documents
-
view
215 -
download
0
Transcript of May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a...
![Page 1: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/1.jpg)
May 27, 2005
Control of stability of intracellular Ca-oscillations and electrical
activity in a network of coupled cells.
Stan GielenDept. of Biophysics
Martijn Kusters
Wilbert van Meerwijk
Dick Ypey
Lex Theuvenet
![Page 2: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/2.jpg)
May 27, 2005
Overview• Summary of Ca-dynamics in NRK cell• Dynamics of Ca-oscillations and action potentials• coupling between Ca-oscillations and action
potentials• Stability of Ca-dynamics in the cell• Alternative model for cells with IP3-oscillations• Coupling between two oscillators• Propagation of electrical activity in network of
layers– oscillators as pacemakers which initiate propagation ?– instability due to coupling ?
![Page 3: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/3.jpg)
May 27, 2005
Model for Normal Rat Kidney Cell
• NRK-cell = fibroblast
• similar to Cells of Cajal
• NRK cells form a network coupled by gap-junctions
![Page 4: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/4.jpg)
May 27, 2005
Model for Membrane NRK cell
![Page 5: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/5.jpg)
May 27, 2005
Components of the model
CacytBCacyt
B
Caex
GCaLClex
GCl(Ca)
KcytGKir
Gleak
ATPPMCA
CaER
(0.1 μM)
(1000 μM)
(1000 μM)
![Page 6: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/6.jpg)
May 27, 2005
This model focusses on the dynamics of the cell membrane, including the L-type Ca-channel and other ion channels with the following components:
• PMCA pump : pump Ca out of cytosol into extracellular space
• Ca2+ L-type channel: Vca-L = +55 mV• Cl(Ca) channel : VCl = -20 mV• Leak channel• Kir channel : VK = -75 mV• Ca-buffer in the cytosol Cacyt BCacyt
B
Caex
GCaLClex
GCl(Ca)
KcytGKir
Gleak
PMCA
CaER
![Page 7: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/7.jpg)
May 27, 2005
Components of the model for the NRK Membrane
• Leak current
• Potassium channel
• PMCA-pomp
PMCAcyt
cytPMCAPMCA
OK
K
KKK
KK
KKK
KOKK
leakleakleak
KCa
CaCJ
K
F
RTE
EV
EVEV
EV
EVK
GI
EVGI
)120
ln(1000
))50(06.0exp(1
)10(0002.0exp))100(0002.0exp(3
})50{06.0exp(1
1.0
)(4.5
)(
![Page 8: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/8.jpg)
May 27, 2005
Components of the model for the NRK Membrane
• Ca2+ L type channel
• Cl(Ca) kanaal)(
1
1
))}10(0337.0{exp(0197.002.0
01.0
)24.5/)37exp((1
1
)10(035.0
))9.5/)10(exp(1(01.0
)24.5/)15(exp(1
1
)(
)()()(
2
)()()(
CaClClcyt
cytCaClCaCl
cytwCaCa
h
m
LCaCaLCaLCa
EVKCa
CaGI
CaKw
V
Vh
V
Vm
Vm
EVwhmGI
![Page 9: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/9.jpg)
May 27, 2005
Current clamp Ipulse=6 pA• When we current clamp, the activation gate of the Ca L
type opens, giving rise to an inflow of Ca through the Ca L type channel.
• As a consequence, an action potential will be generated
Cacyt
BCacyt
B
Caex
GCaLGCl(Ca)
K
GKir
Gleak
PMCA
CaER
![Page 10: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/10.jpg)
May 27, 2005
Current clamp Ipulse=6 pAAction potentialCacyt
Buffered Ca
PMCA current
IK
ICl
ILeak
)20(
)55(
)()(
)()(
mVVKCa
CaGI
mVVwhmGI
Clcyt
cytCaClCaCl
CaLCaLCa
PMCAcyt
cytPMCAPMCA
KKK
KOKK
leakleakleak
KCa
CaCJ
EVK
GI
EVGI
)(4.5
)(
![Page 11: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/11.jpg)
May 27, 2005
Current clamp Ipulse=6 pAAction potentialCacyt
Buffered Ca
PMCA current
IK
ICl
ILeak
Inflow of Ca through L-type Ca channel
Plateau due to Nernst potential of Ca-dependent Cl-channel
![Page 12: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/12.jpg)
May 27, 2005
Current clamp Ipulse=6 pAAction potentialCacyt
Buffered Ca
PMCA current
IK
ICl
ILeak
)20(
)55(
)()(
)()(
mVVKCa
CaGI
mVVwhmGI
Clcyt
cytCaClCaCl
CaLCaLCa
PMCAcyt
cytPMCAPMCA
KKK
KOKK
leakleakleak
KCa
CaCJ
EVK
GI
EVGI
)(4.5
)(
Important !
![Page 13: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/13.jpg)
May 27, 2005
Adding a Ca2+ buffer eliminates the plateau
De Roos et al. 1998
![Page 14: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/14.jpg)
May 27, 2005
The effect of a Ca-bufferWith Ca buffer Without Ca buffer
Shorter plateau-phase
![Page 15: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/15.jpg)
May 27, 2005
Model for intracellular Ca2+-oscillations
![Page 16: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/16.jpg)
May 27, 2005
Model for Ca-oscillations from ER
Glek
CaER
Cacyt
BCacyt
BGlk
Glek
ATP PMCA
IP3 receptor
ATP
ATP
SERCA
• SERCA pump• IP3-receptor• leakage of Ca from the ER into the cytosol• PMCA pump• leakage of Ca from extracellular space into the cytosol• Ca-buffer in the cytosol
(0.1 μM)
(1000 μM)
![Page 17: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/17.jpg)
May 27, 2005
This model focusses on the dynamics of Ca in the ER and cytosol by transport through the IP3 receptor. The model has the following components:
• SERCA pump• IP3-receptor• leakage of Ca from the ER into the cytosol• PMCA pump• leakage of Ca from extracellular space into the
cytosol• Ca-buffer in the cytosol
![Page 18: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/18.jpg)
May 27, 2005
Components of the model for the IP3-oscillator
• IP3-receptor
• Leakage from ER• SERCA-pomp
cytwIP
w
w
cytwIP
w
wIPw
wIPfIPcyt
cyt
CaKIP
IPK
CaKIP
IPK
KIPIP
K
w
KIP
IP
KCa
Caf
1.03
320
333
3
3
3
3
32
32
313
)(,, cytERERleakERleak CaCaCJ
)(3333 cytERIPIP CaCawfCJ
A conversion factor of 0.1 transforms an increase/decrease of CaER into a decrease/increase of Cacyt.
![Page 19: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/19.jpg)
May 27, 2005
Intracellular Ca-oscillations
Harks et al., 2004
![Page 20: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/20.jpg)
May 27, 2005
Stability analysis of IP3 receptor
cytwIP
w
w
cytwIP
w
wIPw
wIPfIPcyt
cyt
CaKIP
IPK
CaKIP
IPK
KIP
IPK
w
KIP
IP
KCa
Caf
1.03
320
3
33
3
3
3
3
32
32
313
![Page 21: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/21.jpg)
May 27, 2005
Ca-oscillations as a function of IP3
![Page 22: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/22.jpg)
May 27, 2005
IP3-mediated calcium oscillations
Ca E
RBuf
fere
d C
aBuffered Ca
CacytC
a cyt
CaER
JPMCA,JSOC,JLeakJSERCA, JIP3
![Page 23: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/23.jpg)
May 27, 2005
Concentration IP3 low high
IP3-mediated calcium oscillations
CaERCaERCacyt CacytBuffered Ca Buffered Ca
JSERCA, JIP3JSERCA, JIP3JPMCA,JSOC,JLeak JPMCA,JSOC,JLeak
![Page 24: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/24.jpg)
May 27, 2005
Overview• Summary of Ca-dynamics in NRK cell• Dynamics of Ca-oscillations and action potentials• coupling between Ca-oscillations and action
potentials• Stability of Ca-dynamics in the cell• Alternative model for cells with IP3-oscillations• Coupling between two oscillators• Propagation of electrical activity in network of
layers– oscillators as pacemakers which initiate propagation ?– instability due to coupling ?
![Page 25: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/25.jpg)
May 27, 2005
Stability of Ca-dynamics in the cell
Whole cell modelAction potentials
Ca-oscillations
![Page 26: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/26.jpg)
May 27, 2005
CacytBCacyt
B
IP3
Caex
GCaLClex
GCl(Ca)
KcytGKir
Glk
GCalk PMCA
CaerSERCA
IP3RJCalker
Complete Model
![Page 27: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/27.jpg)
May 27, 2005
steady-state behavior
Without IP3, the steady-state is easily found by solving JSERCA=Jleak,ER and JPMCA=Jleak,membrane
This gives a single, stable solution for Cacyt and CaER :
Cacytosol = 0.1 μM; CaER= 1300 μM
)1000(maxcytlk
PMCAcyt
cytPMCA CaG
KCa
CaI
SERCAcyt
cytSERCAcytERleak KCa
CaJCaCaG
max)(
ER/cytosol:
membrane/cytosol:
![Page 28: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/28.jpg)
May 27, 2005
Stability of Ca2+ concentrations
Cacyt
Caex (1000 μM)
GCalk PMCA
CaerSERCAJCalker
Cacyt
GCalk PMCA
CaerSERCAJCalker
Action potential triggers Ca oscillation Ca oscillation triggers action potential
Caex (1000 μM)
![Page 29: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/29.jpg)
May 27, 2005
CacytBCacyt
B
IP3
Caex
GCaLClex
GCl(Ca)
KcytGKir
Glk
GCalk PMCA
CaerSERCA
IP3RJCalker
Additional channel to stabilize Ca-dynamics
GSOC
![Page 30: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/30.jpg)
May 27, 2005
Whole cell model with SOC/CRAC channel
Action potentials
Ca-oscillations
![Page 31: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/31.jpg)
May 27, 2005
Components of the model
Mem
bran
e po
tent
ial
Cacytosol (μMol)
dV/dt = 0
dCacyt/dt=0
IP3 = 0
Stable attractor
![Page 32: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/32.jpg)
May 27, 2005
Components of the model
Mem
bran
e po
tent
ial
dV/dt = 0
dCacyt/dt=0
IP3 receptor oscillates
No stable attractor
0 0.5 1 1.5 2
Red for ca
80
60
40
20
0
20
40
60
eulB
rofV
ip3 1
Cacytosol (μM)
![Page 33: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/33.jpg)
May 27, 2005
Components of the model
dV/dt = 0
dCacyt/dt=0
IP3 high
Stable attractor at – 20 mV
0 0.5 1 1.5 2
Red for ca
80
60
40
20
0
20
40
60
eulB
rofV
ip3 3
Mem
bran
e po
tent
ial
Cacytosol (μMol)
![Page 34: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/34.jpg)
May 27, 2005
Stability analysis of IP3 receptor
cytwIP
w
w
cytwIP
w
wIPw
wIPfIPcyt
cyt
CaKIP
IPK
CaKIP
IPK
KIP
IPK
w
KIP
IP
KCa
Caf
1.03
320
3
33
3
3
3
3
32
32
313
![Page 35: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/35.jpg)
May 27, 2005
Summary
• Stability of Ca-dynamics for all possible natural conditions requires a coupling between Ca-concentration in ER and extracellular Ca.
• Without IP3: stable condition corresponds to V=-70 mV; Cacyt=0.1 μM
• Higher IP3 concentrations provide oscillations or stable point at V= -20 mV
![Page 36: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/36.jpg)
May 27, 2005
Overview• Summary of Ca-dynamics in NRK cell• Dynamics of Ca-oscillations and action potentials• coupling between Ca-oscillations and action
potentials• Stability of Ca-dynamics in the cell• Alternative model for cells with IP3-oscillations• Coupling between two oscillators• Propagation of electrical activity in network of
layers– oscillators as pacemakers which initiate propagation ?– instability due to coupling ?
![Page 37: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/37.jpg)
May 27, 2005
Alternative model for coupling between IP3-oscillator
(Ca-oscillations) and membrane oscillator (action potentials)
![Page 38: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/38.jpg)
May 27, 2005
ProblemMany cell types do not oscillate in isolation, but do so in a
synchronized manner only when electrically coupled in a network (e.g. β-pancreatic cells in islets of Langerhans and aortic smooth muscle cells).– Cells in isolation are quiet or oscillate at lower
frequencies.Paradox: If identical cells oscillate in phase, there are no
currents ! How then can electrical coupling be crucial for the synchronous oscillations ? Moreover: if there are phase differences, they will be eliminated by the electrical coupling !
![Page 39: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/39.jpg)
May 27, 2005
Basic mechanism
0),(
),(
),(
cyt
ERcyt
ERcytER
cytERcytcyt
dCa
CaCadJ
CaCaJdt
dCa
UKCaCaCaJdt
dCa
J(Cacyt,CaER) = interaction term between Ca concentrations
with reflecting Ca-induced Ca-release
KCacyt = efflux of Ca from cell
U = constant, Ca-mediated electrical current
0),(
cyt
ERcyt
dCa
CaCadJ
Loewenstein & Sompolinsky, PNAS, 2001
![Page 40: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/40.jpg)
May 27, 2005
Calcium and Voltage oscillationsin non-excitable cell
Cytosolic Ca (μM) Ca in stores (μM)
Rest-state is unstable fixed-point
Small perturbations in cytosolic Ca cause oscillations
Loewenstein et al., PNAS 98, 2001
![Page 41: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/41.jpg)
May 27, 2005
Calcium and Voltage oscillationsCytosolic Ca (μM) Ca in stores (μM)
Non-excitable cell
Excitable cell
with Voltage-dependent Ca-current en Kca channel
IK_Ca hyperpolarizes membrane potential, which de-activates Ca-influx into cell
However, adding a shunt conductance
destabilizes the fixed point
Hyperpolarization decreases by electrical coupling )( ji
jij
icoupling VVgI
![Page 42: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/42.jpg)
May 27, 2005
Calcium and Voltage oscillationsCytosolic Ca (μM) Ca in stores (μM)
Excitable cell
with Voltage-dependent Ca-current en Kca channel
Addition of ashunt conductance
1. Reduces the effect of Cacyt on membranbe potential
2. Suppresses efficacy of negative feedback by IK_Ca
3. Enables oscillations
with Voltage-dependent Ca-current en Kca channel but with shunt conductance
![Page 43: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/43.jpg)
May 27, 2005
Voltage and Ca oscillations in network of two electrically coupled cells
Ca oscillations out-of-phase; electrical oscillations in-phase at double frequency
Hyperpolarization due to Ca-influx
Hyperpolarization due to electrical coupling
![Page 44: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/44.jpg)
May 27, 2005
Multi-stability in network with 6 coupled
cells.
Cell
123456
123456
In a large network different realizations of out-of-phase calcium oscillations are possible and therefore the network possesses many stable states. The stable state in which the system will eventually settle is determined by the initial conditions.
Note the differences in membrane potential !
![Page 45: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/45.jpg)
May 27, 2005
Summary• Cells are
– intrinsically stable (near –70 mV ; Loewenstein et al. PNAS 2001) or
– intrinsically oscillating ?
• Electrical coupling – enables oscillations and propagation of activity to
otherwise silent cells or – disables oscillations and propagating activity in a
network of pacemaker cells ?
• Ca oscillations out of phase ! Why ?
![Page 46: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/46.jpg)
May 27, 2005
Overview• Summary of Ca-dynamics in NRK cell• Dynamics of Ca-oscillations and action potentials• coupling between Ca-oscillations and action
potentials• Stability of Ca-dynamics in the cell• Alternative model for cells with IP3-oscillations• Coupling between two oscillators• Propagation of electrical activity in network of
layers– oscillators as pacemakers which initiate propagation ?– instability due to coupling ?
![Page 47: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/47.jpg)
May 27, 2005
Coupling between two oscillators
Inhibition and electrical coupling
![Page 48: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/48.jpg)
May 27, 2005
Neuronal synchronization due to external inputT
ΔTΔ(θ)= ΔT/T
Synaptic input
![Page 49: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/49.jpg)
May 27, 2005
Neuronal synchronizationT
ΔTΔ(θ)= ΔT/T
Phase shift as a function of the relative phase of the external input.
Phase advance
Hyperpolarizing stimulus
Depolarizing stimulus
![Page 50: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/50.jpg)
May 27, 2005
Neuronal synchronizationT
ΔTΔ(θ)= ΔT/T
Suppose:
• T = 95 ms
• external trigger: every 76 ms
• Synchronization when ΔT/T=(95-76)/95=0.2
• external trigger at time 0.7x95 ms = 66.5 ms
![Page 51: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/51.jpg)
May 27, 2005
Inhibitory couplingfor two identical leaky-integrate-and-fire neurons
Out-of-phase stable In-phase stable
Lewis&Rinzel, J. Comp. Neurosci, 2003
![Page 52: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/52.jpg)
May 27, 2005
Phase-shift functionfor inhibitory coupling
0)( *
d
dG
for stable attractor
Increasing constant input to the LIF-neurons
I=1.2
I=1.4
I=1.6
![Page 53: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/53.jpg)
May 27, 2005
Bifurcation diagram for two identical LIF-neurons with inhibitory coupling
![Page 54: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/54.jpg)
May 27, 2005
Bifurcation diagram for two identical LIF-neurons with inhibitory coupling
Time constant for inhibitory synaps
![Page 55: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/55.jpg)
May 27, 2005
Electrical coupling for spiking neuronsby gap junctional coupling
Out-of-phase stable In-phase stable
![Page 56: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/56.jpg)
May 27, 2005
Phase-shift functionfor electrical coupling
effect of supra-threshold part of spike tends to synchronize activity
effect of sub-threshold part of spike tends to desynchronize activity
-70 mV
0 mV
+40 mV1.
2.1. 2.
![Page 57: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/57.jpg)
May 27, 2005
Phase-shift functionfor electrical coupling
I=1.05
I=1.15
I=1.25
effect of supra-threshold part of spike tends to synchronize activity
effect of sub-threshold part of spike tends to desynchronize activity
effect of both components
![Page 58: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/58.jpg)
May 27, 2005
Bifurcation diagram for two identical LIF-neurons with electrical coupling
![Page 59: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/59.jpg)
May 27, 2005
Bifurcation diagram for two identical LIF-neurons with electrical coupling
![Page 60: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/60.jpg)
May 27, 2005
If natural frequencies do not matchTime courses of hypathocyte x1 (solid line) and of x2 (dashed line) at P1=1.5 μM and P2=2.5 μM. (a) Harmonic locking of 1:3 (γCA=0.025 s-1); (b) harmonic lockingof 1:2 (γCA=0.05 s-1); (c) phase locking of 1:1 (γCA=0.09 s-1). (d) Devil’s staircase, a ratio N/M (where N is the spike number of x1 and M is the spike numberof x2) as a function of the coupling strength γCA at given IP3 level: P1=1.5 μM, P2=2.5 μM.
Wu et al., Biophys. Chem. 113, 2005Coupling strength
![Page 61: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/61.jpg)
May 27, 2005
Bifurcation diagram for two identical LIF-neurons with inhibitory and electrical coupling
Inhibitory coupling only
Electrical coupling only
![Page 62: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/62.jpg)
May 27, 2005
Electrical coupling in addition to synaptic (inhibitory) interactions
anti-phase, weak electrical coupling
in-phase , strong electrical coupling
no electrical coupling
anti-phase , weak electrical coupling
in-phase , strong electrical coupling
Brem & Rinzel, J. Neurophysiol. 91, 2004
![Page 63: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/63.jpg)
May 27, 2005
Anti-phase and in-phase both stable
Stable in-phase
Stable anti-phase
Electrical coupling in addition to synaptic interactions
The stronger is the synaptic inhibition, the larger is the electrical coupling required to stabilize in-phase behavior
![Page 64: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/64.jpg)
May 27, 2005
Summary
• Gap-junctions between two cells tend to synchronize the two oscillators
• synchronizing effect is stronger when there is a plateau phase in the action potential
![Page 65: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/65.jpg)
May 27, 2005
Overview• Summary of Ca-dynamics in NRK cell• Dynamics of Ca-oscillations and action potentials• coupling between Ca-oscillations and action
potentials• Stability of Ca-dynamics in the cell• Alternative model for cells with IP3-oscillations• Coupling between two oscillators• Propagation of electrical activity in network of
layers– oscillators as pacemakers which initiate propagation ?– instability due to coupling ?
![Page 66: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/66.jpg)
May 27, 2005
What happens for two pacemaker cells with excitatory and gap-
junctional coupling ?
![Page 67: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/67.jpg)
May 27, 2005
Two pacemaker cells
![Page 68: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/68.jpg)
May 27, 2005
Synchronization of two oscillators
No coupling
Small conductance gap junction
Small conductance gap junction
![Page 69: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/69.jpg)
May 27, 2005
Simple result for excitatory and electrical coupling
• Two pacemaker cells synchronize easily
![Page 70: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/70.jpg)
May 27, 2005
Synchronization of activity in a network of cells
![Page 71: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/71.jpg)
May 27, 2005
Network of NRK-cells
![Page 72: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/72.jpg)
May 27, 2005
One pacemaker, surrounded by 6 followers
![Page 73: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/73.jpg)
May 27, 2005
Two pacemaker cells
Ri
Rgap
RcellV
![Page 74: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/74.jpg)
May 27, 2005
Network of NRK-cells
Ri
Rgap
Rcell
Rgap
Rcell
Rgap
Rcell
Experimental observation: a single pacemaker cell cannot initiate propagation of action potential firing
![Page 75: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/75.jpg)
May 27, 2005
Resistance of gap-junction should not be too high and not
too low !
Ri
Rgap
Rcell
Rgap
Rcell
Rgap
Rcell
In the heart: Rcell is high !
![Page 76: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/76.jpg)
May 27, 2005
Synchronization in a network of different coupled oscillators
![Page 77: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/77.jpg)
May 27, 2005
Spontaneous oscillations and synchronization in NRK networks
Caer
Casyst
Membrane
potential
NRK cell with intracellular (IP3) oscillator and plasma membrane
Network
with NRK cells
Oscillations and synchronization
![Page 78: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/78.jpg)
May 27, 2005
Standing problems• Cells are intrinsically stable, but become unstable
due to coupling in a network ?• Or: cells are unstable but synchronize in a network
to act as pacemakers for propagating activity ?• What is the role of electrical/gap-junctional
coupling and Ca-diffusion through gap junctions in propagation of action potential firing ?
• How to recognize pacemakers and followers ?• Pace-makers seem to “move” in a network
![Page 79: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/79.jpg)
May 27, 2005
![Page 80: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/80.jpg)
May 27, 2005
CacytBCacyt
B
IP3
Caex
GCaLClex
GCl(Ca)
KcytGKir
Glk
GCalk PMCA
CaerSERCA
IP3RJCalker
Complete model
GSOC
![Page 81: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/81.jpg)
May 27, 2005
Further topics for study
• Compartimentalization:
– coupling of ER with cell membrane for store-operated channels
– discrete sources and sinks (stores)
– discrete channels : distance between channel clusters is larger than the diffusion length of free Ca2+
• stability of intracellular Ca2+ control
• relation between stochastic character of channel dynamics and deterministic periodic behavior of Ca-oscillations
![Page 82: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/82.jpg)
May 27, 2005
References
• Falcke (2004) Reading the patterns in living cells —the physics of Ca2+ signaling. Advances in Physics, 53, 255–440
• Loewenstein, Yarom, Sompolinsky (2001) The generation of oscillations in networks of electrically coupled cells. PNAS 98, 8095-8100.
![Page 83: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/83.jpg)
May 27, 2005
Components of the model for the NRK Membrane
• CRAC kanaal• Ca2+ L type channel
• Cl(Ca) kanaal)(
11
1
))}10(0337.0{exp(0197.002.001.0
)24.5/)37exp((11
)10(035.0))9.5/)10(exp(1(01.0
)24.5/)15(exp(11
)(
)(1
)/(1
)()()(
2
)()()(
CaClClcyt
cytCaClCaCl
cytCa
h
m
LCaCaLCaLCa
CaCRACER
CRACCRAC
EVKCa
CaGI
Caw
V
Vh
VVm
Vm
EVwhmGI
EVKCa
CconvfluxI
![Page 84: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/84.jpg)
May 27, 2005
Components of the model in the cell membrane
• CRAC channel
• Leakage into cytosol
• PMCA-pomp
)1000( cytlklk CaCJ
PMCAcyt
cytPMCAPMCA
KCa
CaCJ
)(1 Nernst
CaCRACER
CRACCRAC EVKCa
CJ
![Page 85: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/85.jpg)
May 27, 2005
Overview of parameter values
MK
pFC
MK
nSG
nSG
nSG
nSG
VE
VE
VE
O
m
Cl
CaCl
LCa
K
leak
NernstCaCl
NernstLCa
Nernstleak
35
20
35
0.10
50.0
2.2
05.0
02.0
05.0
0
)(
)(
)(
)(
100000123.02
10
55.0
2.0
27.1
06.0
)(032.0
20
/96480
293
molKs kg m31.8
1
1
1
1
-1-1-22
convflux
MK
MsC
MK
MsC
sK
sMK
MTB
molCF
KT
R
CRAC
CRAC
PMCA
PMCA
off
on
MK
MK
MK
sK
MK
sC
sMC
sC
fIP
wIP
wIP
w
SERCA
lek
SERCA
IP
5.0
15
5
1
2.0
002.0
/6.0
10
3
32
31
1
1
13
for membrane for ER
![Page 86: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/86.jpg)
May 27, 2005
Dynamics of IP3 regulated Ca2+ release
![Page 87: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/87.jpg)
May 27, 2005
Ca-oscillations as a function of IP3
![Page 88: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/88.jpg)
May 27, 2005
Oscillations in a large network
![Page 89: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/89.jpg)
May 27, 2005
-150 -100 -50 0 50 100 1500
0.2
0.4
0.6
0.8
1
m(V)
-150 -100 -50 0 50 100 1500
2
4
6
8x 10
-3
m
(V)
m (
s)
-150 -100 -50 0 50 100 1500.2
0.4
0.6
0.8
1
1.2
h(V)
Vclamp (mV)-100 -50 0 50 1000
2
4
6
8
10
h(V)
Vclamp (mV)
h (
s)
Parameter fitting
![Page 90: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/90.jpg)
May 27, 2005
Ca-action potentialstriggered by Ca-release from the ER
GCaL 20 mV
GCl(Ca) -20 mV
GKIR -70 mV
![Page 91: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/91.jpg)
May 27, 2005
Phase diagram for closed-cell model
Sneyd et al., PNAS, 2004
![Page 92: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/92.jpg)
May 27, 2005
Ca2+ is involved in the control of• Muscle contraction• memory storage• egg fertilization• enzyme secretion by acinar cell in pancreas• coordination of cell behavior in the liver• cell apoptosis• second messenger : coding and transfer of information
from cell membrane to nucleus• etc., etc., etc.
Yet, high cytosolic concentrations prohibit normal functioning of the cell. How can this be made compatibel ?
See Martin Falcke, Advances in Physics, 53, 2004
![Page 93: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/93.jpg)
May 27, 2005
Different forms of Ca2+ oscillations
hepatocyte stimulated with norepinephrine
endothelial cellstimulated with histamine
sinusoidal oscillations in a parotid gland
![Page 94: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/94.jpg)
May 27, 2005
Ca-dynamics
• Ca-oscillations in non-excitable cells
• Ca-inflow in excitable cells (action-potential generation) without intracellular Ca-oscillations.
• Ca-oscillations in cells with action-potentials and with IP3-mediated Ca-oscillations.
![Page 95: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/95.jpg)
May 27, 2005
Overview• Summary of Hodgkin-Huxley model• Dynamics of Ca-oscillations and action
potentials• coupling between Ca-oscillations and action
potentials• Stability of Ca-dynamics in the cell• Propagation of electrical activity in network
of layers– oscillators as pacemakers which initiate propagation ?– instability due to coupling ?
![Page 96: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/96.jpg)
May 27, 2005
V mV
0 mV
V mV
0 mV
IC
INa
Membrane voltage equation
-Cm dV/dt = gmax, Nam3h(V-Vna) + gmax, K n4 (V-VK ) + g leak(V-Vleak)
K
![Page 97: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/97.jpg)
May 27, 2005
V (mV)
mmOpen Closedm
m
mProbability:
State:
(1-m)
Channel Open Probability:
dt
dm m)1( m m m
hhdtdh
hh )1(
Gating kinetics
m.m.m.h=m3h
mm
mm
mm
1
![Page 98: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/98.jpg)
May 27, 2005
Actionpotential
![Page 99: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/99.jpg)
May 27, 2005
Simplification of Hodgkin-HuxleyFast variables• membrane potential V• activation rate for Na+
m
Slow variables• activation rate for K+ n• inactivation rate for
Na+ h
-C dV/dt = gNam3h(V-Ena)+gKn4(V-EK)+gL(V-EL) + I
dm/dt = αm(1-m)-βmm
dh/dt = αh(1-h)-βhh
dn/dt = αn(1-n)-βnn
![Page 100: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/100.jpg)
May 27, 2005
Phase diagram for the Morris-Lecar model
![Page 101: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/101.jpg)
May 27, 2005
Phase diagram
![Page 102: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/102.jpg)
May 27, 2005
Phase diagram of the Morris-Lecar model
![Page 103: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/103.jpg)
May 27, 2005
Buffer dynamics
with
Kon = 0.032 (μMol s)-1
Koff = 0.06 s-1
CaBBCacyt
![Page 104: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/104.jpg)
May 27, 2005
Phase-plane plot for membrane dynamics (Morris-Lecar model)
![Page 105: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/105.jpg)
May 27, 2005
Ca L type channel activation (m∞) and inactivation (h ∞)
m∞
h ∞
V (mV)
![Page 106: May 27, 2005 Control of stability of intracellular Ca-oscillations and electrical activity in a network of coupled cells. Stan Gielen Dept. of Biophysics.](https://reader035.fdocuments.in/reader035/viewer/2022070416/5697c01b1a28abf838ccf8c5/html5/thumbnails/106.jpg)
May 27, 2005
The effect of Kon on the action potentialKon = 3.2 (μMol.s)-1Kon = 0.032 (μMol.s)-1
Kon = 0.32 (μMol.s)-1
Shorter APMore Ca buffered
Longer AP
All Ca buffered