We went through this in my class last week and it doesn't make sense to me at all.

It's small and it diffuses in and out so easily so wouldn't it diffuse out quickly and thus not be a local signal? Or where it's stored in the RER does that change things?

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    $\begingroup$ Diffuse out of where? Ions cannot pass through the membrane. $\endgroup$ – canadianer Apr 5 '17 at 4:34
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    $\begingroup$ I may try to write up a full answer later, but for a quick answer: calcium does not diffuse out of a cell ever, it actually takes a lot of effort for cells to keep their calcium concentrations so low. Instead, cells have a lot of calcium buffering capacity, so when calcium comes in it only stays free temporarily. That's when it has the opportunity to have influence. As it lingers and diffuses away from where it influxes, it is constantly being picked up by chelators, so it doesn't have a chance to diffuse away from a local signal at any high concentration. $\endgroup$ – Bryan Krause Apr 5 '17 at 4:39
  • $\begingroup$ Ions can only pass through channels in lipid membranes, such as voltage gated calcium channels at presynaptic membranes. That might clear up a bit of the confusion. Chelators bind free calcium ions, preventing them from interacting with other signalling molecules. $\endgroup$ – Oliver Houston Jul 27 '17 at 8:28
  • $\begingroup$ @BryanKrause — Please follow the injunction you read when you click on the comment box: do not use comments for answers. It breaks the SE model. $\endgroup$ – David Dec 23 '17 at 19:49

As @BryanKrause says in his comment, net flux of calcium would not ever be from inside the cell to outside the cell. There is a large gradient the other direction. Per Berg, the cytosolic concentration of calcium in a resting cell is on the order of 100nM, while extracellular concentration is in the mM range.

Signalling occurs when channels open up and allow $Ca^{2+}$ to diffuse down that very steep electrochemical gradient (from extracellular or topologically similar sources, e.g., the endoplasmic reticulum).

At least part of your question seems to involve a concern that the signal would not be very long lived. Though your concern about it diffusing out of the cell isn't warranted, the question about the time dynamics of calcium signalling is interesting. Calcium signals are, in fact, often very brief (though in other cases they last much longer). This is actually a benefit, and is one reason these signals can have very localized, very brief effects. For localized membrane fusion events, e.g., exocytosis, the signal lasts on the order of microseconds. The control of the time and position of a calcium signal involves a large number of players, including sequestering proteins, various compartments and stores, and tight control of the balance between calcium on and calcium off signals. It is discussed in this nature review, and summarized in this simplified figure:

enter image description here

You might also be interested in looking at some videos of calcium signalling. There are a number on youtube. This is one example


Calcium ions hold a +2 charge, and thus are unable to diffuse through lipid membranes. It is stored in the ER, and released to act as a signaling molecule in the cytoplasm. Being unable to cross membranes it remains in the cytoplasm until it is actively transported back into the ER.

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    $\begingroup$ Overall, decent answer, please add some references though. $\endgroup$ – L.B. Jul 26 '17 at 17:11

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