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Printable Handouts
Navigable Slide Index
- Introduction
- A mitochondrial store with Ca2+-dependent uptake and saturable release
- Evidence that sympathetic neurons contain a FCCP-sensitive Ca2+ store
- Observations indicating that the FCCP-sensitive store is mitochondrial
- *Origin of the rate description for Juni
- *Voltage-dependence of Juni
- Responses to stimulation, steady states and stability
- Qualitative properties of the nonlinear system flux/[Ca2+] relations
- JMito depends on both [Ca2+]i and [Ca2+]Mito (1)
- JMito depends on both [Ca2+]i and [Ca2+]Mito (2)
- Nullcline analysis
- Effects of stimulated Ca2+ entry
- Graded responses to strong stimuli of different durations
- ci and cs trajectory during and after stimulation
- Impact of mitochondrial Ca2+ transport
- A second recap of modelling Ca2+ stores
- Spatially nonuniform Ca2+ signals
- General concepts, space and time scales
- Spatial hierarchy of Ca2+ signals
- The diffusion equation
- Ca2+ responses in spherically symmetrical cells
- Effect of passive Ca2+ diffusion across the plasma membrane
- Effect of stimulated Ca2+ entry on [Ca2+]i
- Methods for analyzing Ca2+ handling properties in intact cells
- Measuring the total cytoplasmic Ca2+ flux
- Dissecting the total Ca2+ flux into its components
- Example: one store with a unidirectional Ca2+ uptake pathway
- Determining the inhibitor-sensitive component of the total Ca2+ flux
- *Characterization of cytoplasmic Ca2+ buffering strength
- Developing an experimentally-based model of Ca2+ dynamics in sympathetic neurons
- Experimental characterization of cytoplasmic Ca2+ buffering strength
- Case 1: PM Ca2+ transport, cytoplasmic Ca2+ buffering
- Case 2: contributions from the mitochondrial uniporter
- Case 2: contributions from the mitochondrial NCX
- Full model: Stimulated response to steady depolarization
- Full model: Stimulated response to evoked action potential firing
- Summary and conclusions
- Reading
- Thank you!
Topics Covered
- FCCP-sensitive Ca2+ stores
- The mitochondrial uniporter (MCU)
- Mitochondrial Ca2+ flux
- Spatially nonuniform Ca2+ signals
- Spatial hierarchy of Ca2+ signals
- The diffusion equation
- Ca2+ responses in spherically symmetrical cells
- Methods for analyzing Ca2+ handling properties in intact cells
- Developing an experimentally based model of Ca2+ dynamics in sympathetic neurons
Talk Citation
Friel, D. (2021, August 31). Modeling Ca2+ signals: understanding Ca2+ regulatory networks in cells - Ca2+ stores: mitochondria, models of spatially non-uniform Ca2+ signals, applications to analysis of experimental results [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 21, 2024, from https://doi.org/10.69645/HLXW9385.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. David Friel has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Modeling Ca2+ signals: understanding Ca2+ regulatory networks in cells - Ca2+ stores: mitochondria, models of spatially non-uniform Ca2+ signals, applications to analysis of experimental results
Published on August 31, 2021
49 min
A selection of talks on Cell Biology
Transcript
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0:04
We now consider the case where calcium-sensitive calcium channels operate in
a store that maintains a driving force favoring calcium uptake instead of release.
This case is relevant to mitochondria,
another major organelle found in Eukaryotic cells.
Mitochondria maintain a large electrical potential difference
across their inner membrane,
with the internal voltage being 150 to 200 millivolts
lower than the extramitochondrial or cytosolic voltage.
This voltage drop arises through the interplay between
active proton export mediated by pumps that are part of the electron transport chain.
Passive proton re-entry via the ATP synthase,
which is coupled to ATP synthesis.
The inner membrane is also the site of a calcium-permeable channel called the
mitochondrial uniporter where MCU-like ryanodine receptors,
MCU channels open in response to elevations in
the cytosolic calcium concentration and are permeable to calcium.
However, unlike ryanodine receptors,
when these channels open,
they normally mediate the flow of calcium into
the organelle down at a steep electrochemical gradient,
mainly due to the large voltage drop across the inner membrane.
The symbolize approach to modeling mitochondrial calcium handling and
its effect on stimulus evoke calcium responses is to
represent mitochondria as a compartment within the cytosol
exposed to a spatially uniform cytosolic calcium concentration.
As with the description of the ER,
this one pool description of mitochondria lumps together
the effects of a distributed organelle system into a single equivalent pool.
Passive calcium movements across the inner membrane are controlled by
MCU channels and occur at a rate that can be described as the product of two terms,
K uni, which increases with
the calcium concentration and the cytosolic calcium concentration itself.
As will be shown later,
this description is an approximation based on the GHK flux equation,
where the K uni lumps together
the calcium-dependent permeability of
the inner membrane and the electrical driving force on calcium.
More general rate laws can be devised,
but the simple one used here will suffice for giving us a feeling for
the way mitochondrial calcium transport influences cellular calcium dynamics.
There is one more transport pathway.
We must consider the efflux pathway by which mitochondria release calcium,
the main efflux pathway,
and neurons because a sodium-calcium exchanger or NC x,
which releases calcium coupled to sodium entry at a rate that depends
saturable on the intro mitochondrial calcium concentration
and the cytosolic sodium level.
Because the exchange is electrogenic,
transport also depends on the mitochondrial membrane potential.
But since we assume the memory potential is constant,
the voltage will not be explicitly expressed in
the right description because the flux is directed into the cytosol,
our sign convention requires that the flux mediated by NCI is negative.
We now have a description of the net calcium flux between mitochondria and the cytosol.
It's the sum of J uni and J naca.
It is the net calcium flux that determines on a moment-to-moment basis,
the direction of net calcium transport between the mitochondria and
the cytosol and whether mitochondria act as a calcium source or sink.
Note that the model does not include a description of the dynamics
of sodium concentration and mitochondrial membrane potential.
This would require introducing
two more dependent variables which the viewer may consider doing later as an exercise.
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