Reaction of the Calcium pump/channel on a cell due to mechanical stimulation?

[leoflc]

Hi,

I am trying to write a model that simulates calcium input and output based on the induced strain, strain rate, and frequency of the applied strain.

But before I can do that, I am trying to know more about the biophysics of the cell.

How does the calcium pump/channel physically react based on different kind of mechanical stimulation (strain, strain rate, frequency, etc...)?

Thank you very much!

 

[alxm]

How does the calcium pump/channel physically react based on different kind of mechanical stimulation (strain, strain rate, frequency, etc...)?

The enzyme deforms of course. Finding out how it deforms is very non-trivial. You might be able to get decent results from MM/force-field calculations. (OTOH, you might not. Depending on how far from equilibrium you are)

But if you're modeling Ca moving through the thing, I assume you've already got an force-field dynamics model in place?

 

[Andy Resnick]

This is an active area of research (disclaimer, I am one of those doing the research). Very little is currently known, and I hope to provide data which answers those exact questions over the next few years.

Something to keep in mind is keeping your model *physiologically relevant*.

 

[leoflc]

Thanks for the reply!

I'm trying to create an agent based model on bone growth, so that's why I want to understand how Ca is moving in and out of the cells.

So I am thinking about to assume the followings, but I'm not sure if they are physiologically relevant:

The Ca induced into the cell due to strain: a S-curve that increases as strain increases, and plateau (100%) after some strain

The Ca induced into the cell due to strain rate: it affects how fast the same S-curve will reach 100% (the slope for the S-curve).
Example: (same strain and frequency)
at strain 10, strain rate 0.01, the Ca input will be 80%
at strain 10, strain rate 0.03, the Ca input will be 100%

The Ca induced into the cell due to strain frequency: will increase the Ca input (multiply the Ca induced due to strain, strain rate)
Example:
at strain 5, strain rate 0.01, frequency 0.5Hz, the Ca input will be 25%
at strain 5, strain rate 0.01, frequency 1Hz, the Ca input will be 50%
at strain 5, strain rate 0.01, frequency 2Hz, the Ca input will be 100%
at strain 5, strain rate 0.01, frequency 5Hz, the Ca input will be 100%

The Ca removed from the cell: a S-curve function that increase as strain increase.

Are these assumptions physiologically relevant?

Thanks a lot!

 

[alxm]

I'm trying to create an agent based model on bone growth, so that's why I want to understand how Ca is moving in and out of the cells.

Okay. Well it sounds then as if your hypothesis is that stress on the calcium channels would directly cause increased calcium uptake and bone growth.
To be blunt, I think that would be a ludicrous idea. Practically nothing in biochemistry is ever that simple and direct. Bone growth and calcium uptake is no doubt regulated by dozens of cofactors and hormones, etc. Which in turn probably regulate the expression of certain genes which then cause growth. We almost certainly don't know everything that's involved, much less how it works. (It's obviously not as simple as a question of calcium concentrations - Estrogen does more to fight osteoporosis in elderly women than drinking milk does. )

I'm no expert on ion channels, but I've once had the pleasure of talking to Roddy MacKinnon, who is. The K+ channels he studied have evolved a very precise geometry in order to only allow their specific ion to pass through. Any strain that would induce a change, if only a small one, in that geometry, would probably lead to the channel loosing function.

 

[Andy Resnick]

Thanks for the reply!

I'm trying to create an agent based model on bone growth, so that's why I want to understand how Ca is moving in and out of the cells.

So I am thinking about to assume the followings, but I'm not sure if they are physiologically relevant:

The Ca induced into the cell due to strain: a S-curve that increases as strain increases, and plateau (100%) after some strain

The Ca induced into the cell due to strain rate: it affects how fast the same S-curve will reach 100% (the slope for the S-curve).
Example: (same strain and frequency)
at strain 10, strain rate 0.01, the Ca input will be 80%
at strain 10, strain rate 0.03, the Ca input will be 100%

The Ca induced into the cell due to strain frequency: will increase the Ca input (multiply the Ca induced due to strain, strain rate)
Example:
at strain 5, strain rate 0.01, frequency 0.5Hz, the Ca input will be 25%
at strain 5, strain rate 0.01, frequency 1Hz, the Ca input will be 50%
at strain 5, strain rate 0.01, frequency 2Hz, the Ca input will be 100%
at strain 5, strain rate 0.01, frequency 5Hz, the Ca input will be 100%

The Ca removed from the cell: a S-curve function that increase as strain increase.

Are these assumptions physiologically relevant?

Thanks a lot!

I need to think a little about what you are proposing, since I don't think the data has yet been taken- these are exactly the questions I am asking: is the cell sensitive to strain or strain rate, what sort of time-dependent responses are there, etc. etc..

As far as your numbers, There is some data out there for hemodynamics, less for flow within bones. Timescales can vary from ~100 Hz (heatbeat of a mouse) to sub-Hz.

One thing to keep in mind is that Ca is also a signalling molecule; the way cells shuttle Ca++ for non-signalling (i.e. resorption through kidney, bone remodeling, etc) is to sequester the Ca++ with chaperone proteins and keep it isolated from the ER stores. I'm not sure of the details, tho. When a Ca++ channel opens, the usual view (AFAIK) is that a signalling cascade is activated via calcium-induced-calcium-release (ryanodine receptors in the ER). Finally, it's not clear if the strain acts directly on the channel (like a voltage-gated channel), or if the channel opens in response to a mechanosensitive protein becoming activated.

Does that help?