Welcome to the world of calcium signalling. This webpage will break down many facets of calcium signalling within cells including entry, compartmentalisation and release of calcium ions, into short digestible chunks. Images are included, these can be enlarged by clicking if there is any difficulty during viewing.
As humans we have to adapt to changing seasons, by wearing a coat in the winter for example. Cells behave in a similar manner in that they also have to adapt to changes in their environment. They do this by relaying environmental changes as 'signals' to their interior - termed signal transduction. So where do calcium ions come into this? In cells, calcium ions can act as second messengers. Second messengers help 'transduce' the signal inside the cell, in order to facilitate a change in cell behaviour.
SIGNAL (ENVIRONMENTAL CHANGE) ----> CELL ----> SIGNAL TRANSDUCTION ----> CHANGE IN CELL BEHAVIOUR
Calcium ions regulate many cellular activities, examples include:
Calcium signalling is driven by gradients across membranes. How so? Well there are less calcium ions in the cytosol (~100nM) than in the extracellular space (mM). This means that there are more positive calcium ions on the extracellular side of the plasma membrane (NB - Ca2+). As a result of this electrochemical gradient - calcium ions are pulled into the cell to even things out....
However - too much calcium in the cytosol has a toxic effect and spells bad news for the cell. Therefore cells strive to maintain a low cytosolic ca2+ concentration using three main methods.
There are two main methods of calcium extrusion via the plasma membrane
1) Plasma membrane Ca2+/ATPase (PMCA) pumps
Out: 1 Ca In: 2H+ Energy used: 1 ATP
Rate: 30 ions per second (high affinity for calcium)
2) Exchangers - 2000 Ca per second
Na/Ca K (NCKX) -> Out: Ca and K In: 4Na
Na/Ca (NCX) -> Out: Ca In: 3Na
Exchangers work at faster rates than ATPases. They facilitate rapid changes in calcium concentration - as required in neurons during generation of action potentials.
Pumps - maintain low cytosolic concentrations of calcium over longer durations of time than exchangers.
Calcium needs to be shifted from the cytosol into intracellular stores (if not extruded or chelated). Calcium can be stored in the endoplasmic reticulum/sarcoplasmic reticulum. This requires opening of sarco(endo)plasmic reticulum calcium ATPase (SERCA) pumps. Alternatively, calcium ions can traverse the outer mitochondrial membrane via simple diffusion down a proton gradient. Beyond this they require opening of highly selective mitochondrial calcium (MiCa) uniporter ion channels in order to be sequestered in the mitochondrial lumen.
1) SERCA Pump (to ER/SR) 2) MiCa (to mitochondria)
The third method of removing free calcium ions from the cytosol is to bind them to proteins. These proteins fall under two groups:
Calcium binding sites (EF Hands)
When Calcium is bound to Calmodulin:
Effect of protein-protein interactions
1) Conformational change causing removal of intrinsic autoinhibition eg activation of Ca/Calmodulin dependent kinase and calcineurin.
2) Remodelling of active sites.
3) Dimerisation of proteins.
How does calcineurin work?
Before reviewing calcium signalling pathways, it is important to understand how calcium enters the cytosol from outside the cell. Each entry method has a specific 'gating' mechanism: voltage gated calcium channels, receptor operated channels, cyclic nucleotide gated channels and store-operated channels.
Voltage gated channels
Receptor operated channels
Store operated channels (SOCs)
Stim1 and Orai1
Here is a brief overview of the receptors used in releasing calcium from intracellular stores. This will make the next section a little clearer. The two receptors important for calcium release from the ER are: IP3 receptors and ryanodine receptors (RyR).
Calcium-induced calcium release (CICR)
Voltage gated dihydropyridine receptors (DHPR) respond to voltage changes on the plasma membrane. This response allows calcium to enter the cytosol, however the cytosolic concentration is still very low (uM). Low calcium concentrations cause a change in conformation of the ryanodine receptor, opening its pore to allow calcium from the ER/SR to enter the cytosol. Conversely, if the cytosolic Ca2+ concentration is too high, the RyR remains shut.
Normally, cytosolic calcium concentrations are kept low. However, this can be increased via release from intracellular stores as we have seen above. The main mechanism inducing this release is via the phospholipase C (PLC) pathway. A ligand, for example a hormone, binds a G protein coupled receptor on the membrane (mainly Gq/11 subtype). The alpha subunit is liberated and activates phospholipase C(B) (alternatively receptor tyrosine kinases can activate PLC(y) ).
Phospholipase C pathway
Free cytosolic calcium in this pathway
This may be too complex to understand by text only, therefore I have attached a link: http://bcs.whfreeman.com/lodish5e/content/cat_010/13010-01.htm?v=chapter&i=13010.01&s=13000&n=00010&o this is an animation of what has been described above and may be helpful if there is any difficulty understanding what has been reviewed.
Calcium is a small ion, yet here it has been demonstrated the vast importance it has during signalling in cells. The activities it partakes in is largely controlled by gradients between membranes (especially embedded receptors/channels) in the cell, allowing it to cooperate with proteins it is able to link to. The overall effect of these binding events is to induce a range of potential changes in cell behaviour. The fact it governs so many of the cells activities provides sound reasoning for the extensive research that goes into breaking the locks we have still yet to understand about calcium signalling.
Clapham, D.E. (2007) Calcium signaling. Cell, 131, 1047–1058
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