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messenger
A: Hepatocytes
B: Rat parotid gland
C: Gonadotropes
D: Hamster eggs (post-
fertilization)
E, F: Insulinoma cells
Summary of calcium
homeostasis Ca2+
PM pumps
ICa
RyR
Ca2+ leak
ER IPR
Ca2+-B
serca
(buffering)
Mitochondria
Calcium metabolism in neurons
Calcium excitability
• Both IPR and RyR release calcium in an excitable manner. They
both respond to a calcium challenge by the release of even more
calcium.
mitochondrial buffering
ER fluxes PM fluxes
fluxes
• The specifics of the coupled o.d.e.s depend on which particular model is being used.
∂ [Ca 2+ ]
JCa = −a DCa
∂x
• Discretised concentration change in volume vi:
[Ca ]
2+
i, t +1 [
− Ca 2 + ]
i, t
=DCa
[
ai ,i +1 Ca 2 + ]
i +1,t [
− Ca 2 + ]
i ,t
∆t vi ∆x
• Only parameter: diffusion constant DCa. Depends on ion size and
medium, e.g. DCa (water) ~ 600 µm2/s, DCa (cytoplasm) ~ 200 µm2/s.
Calcium diffusion: spatial discretization
Limitations:
• Localised calcium fluxes → local calcium domains.
• Calcium induced calcium release → calcium waves, calcium sparks.
→ Model 3D diffusion (computationally expensive).
Calcium dynamics: exponentially decaying pool
[
d Ca 2 +]=
I Ca
([ ] [
− β Ca 2+ − Ca 2 + ] )
min
dt 2 Fv
Advantage: only three parameters
• [Ca2+]min baseline calcium concentration ~50nM.
•β decay rate constant, summarises diffusion, buffering,
pumps and exchangers.
•v volume of calcium pool, usually submembrane shell
(relevant for activation of KCa channels).
Limitations:
• Not possible to study calcium dependent processes in the cytoplasm
(e.g. calcium induced calcium release CICR).
• Different KCa channels sense different [Ca2+]?
Possible extension:
• Use several calcium pools with different βi.
Calcium buffers
k1
For each diffusion shell →
→
J
Ca 2+ + B CaB
and each buffer: ←
k2
d [Ca 2+ ]
= −k1[Ca 2+ ][ B] + k2 [CaB ] + J
dt
Four parameters for each buffer:
• Forward and backward rate constants k1 and k2.
• Total concentration [B]T = [B] + [CaB].
• Diffusion constant DB.
∂ Ca
= Dc ∇2Ca − k + Btot (Ca − Cabk ) + σδ (r )
∂t
σ
Ca = e −r / λ + Cabk
4πDc r
Dc
λ=
k + Bbk
EBA vs. RBA
• EBA appropriate when the saturability of mobile buffer is
negligible. For example, this is the case for millimolar
concentrations of Calbindin-D28K in the saccular hair cell.
• RBA appropriate when there is significant saturability of mobile
buffer and when buffer kinetics are fast relative to Ca2+ diffusion.
This is often the case near Ca2+ channels in synapses, and near
IP3 or ryanodine receptors in the ER/SR.
• Smith et al. (2001) did an asymptotic analysis of buffered Ca2+
diffusion near a point source, and determined mathematical
conditions for when RBA or EBA are appropriate.
Endogenous
Troponin-C 90-100 7-300 0.05-3 0
Calmodulin 100-500 37-470 0.2-2.0 32
Calbindin-D28k 20 8.6 0.4-1.0 27
Parvalbumin 6 1 0.00037 36
Exogenous
EGTA 1.5 0.3 0.2 113
BAPTA 600 100 0.1-0.7 95
Fura-2 600 80-100 0.13-0.6 30-95
Ca Green-1 700 170 0.19-0.25 84
Smith (2001)
[ IP3 ] [Ca 2 + ]
m∞ =
[ IP3 ] + K IP3 [Ca 2+ ] + K Ca 2+
• IP3 production in response to metabotropic glutamate receptor activation
can be modelled with an alpha function (analogous to gAMPA):
d [ IP3 ] −t / t
= γ t e peak − β ([ IP3 ] − [ IP3 ]min )
dt