Let's talk about calcium ions

The calcium ions are really important for our cells. A lot of drugs enter into our cells when their molecules make some interaction with calcium ions. We can say that calcium ions are making our cells active. If the love is the reason for people to do things, we can say the ions of calcium are the reason for our cells to work. The main researches were done during 1990 and since that time we are able to say that we know a lot about mechanisms in our cells and ions of calcium are one of the most important elements of those mechanisms.

Wikimedia commonsRoyroydebCC BY-SA 4.0 Structure of cell

The intercellular level of calcium

Scientists discovered that calcium is important for cells when Singer Ringera found out that water from sink can maintain contractions of the heart from the frog much longer than distilled water. The key was in calcium. But calcium is not important only for the natural functions of our body. It's also important when we are sick because a lot of drugs affect our organism through free intracellular concentration of calcium. I will explain those mechanisms and describe the ways in which calcium ions control the functions of our cells.

Calcium ions are mostly situated inside of cell's organelles, especially inside of mitochondria and endoplasmic reticulum (ER) or sarcoplasmic reticulum (SR). The level of free calcium ions is really low (something around 10-7 mol/l). Inside of extracellular fluid, the concentration of calcium ions is something around 2,4 mmol/l. Our organism has three methods to regulate the level of calcium.

1. Mechanisms of calcium entry;

2. Mechanisms of calcium exit;

3. Exchange of calcium ions between cistules and intracellular depot.

Calcium can enter inside our cells through plasma membrane in various ways. For this, the type of calcium channel is the most important. We are talking about three types of calcium channels:

1. Ligand-gated calcium channels or receptor-operated channels (they depend on ligand binding);

2. Voltage-gated channels (they depend on voltage change);

3. Store-operated calcium channels, SOC (they are activated by the discharge of the calcium depot).

Besides this, one of the mechanisms is a sodium-calcium exchange.

Ligand-gated calcium channels

Ligand-gated calcium channel;Wikimedia commonsPublic domain

The ligand-gated cation channels are mostly non-selective. That means that different kinds of cations can go through those channels. The same case happens with calcium ions. They can easily go through. The most important is glutamate receptor called the N-methyl-D-aspartate receptor (or NMDA receptor). It has a high permeability for calcium ions. If this receptor is active, the concentration of calcium ions inside of neurons is high. This can even cause the death of the cell, probably because calcium ions can activate Ca-dependable protease. This process is called excitotoxicity. Scientists believe that this process is taking the main place in some of the most difficult neurodegenerative disorders.

Voltage-gated channels

Voltage channels are highly sensitive for calcium ions. They don’t provide ions of potassium and sodium, but they can help calcium ions to enter in our cells through the membrane when it is depolarized. For example, the membrane is depolarized after the action potential goes through it. There are five types of voltage channels: L (long-lasting), T (transient), N (neither long-lasting nor transient), P and R. L-channels are responsible for regulation of heart contractions or contractions of other smooth muscles. N-channels are important for the release of neurotransmitters and hormones. T-channels allow calcium ions to enter inside of neurons. Other types of channels have similar functions as well.

Store-operated calcium channels

In case that depot of calcium ions inside endoplasmic reticulum is empty, calcium ions will enter inside the cell through store-operated calcium channels. Scientists still cannot find out in which way those channels are related with endoplasmic reticulum in our cells.

Mechanisms of removing calcium from our cells

We saw how calcium can enter inside our cells and how its concentration becomes high. Our organism has its ways to reduce the level of calcium as well. This process depends on one enzyme. We called it Calcium-dependable ATPase. Calcium goes out of the cell and in its place comes sodium. This process is known as Calcium-Sodium exchange.

Wikimedia commonsPhoebus87CC BY 3.0 Structure of calcium-ATPase

How is calcium released from the depot?

There are two types of calcium channels that allow calcium release from the depot. First one is a receptor for inositol trisphosphate and the second one is a receptor for ryanodine. Both of the channels are very sensitive on calcium ions and they are opening faster if the concentration of calcium is high. That means this process is regenerative and after the first initial release of calcium ions, there will be some more release. This is described as releasing in waves.

Calmodulin (CaM)

Calcium controls a lot of cell functions because it regulates the activity of different proteins, as enzymes, channels, transporters, transcription factors (TF). In most cases, calcium ion is binding to the protein which has a role of intermediate between calcium and functional protein. There are different proteins which have this role, and one of the most important is calmodulin. Calmodulin can regulate almost 40 different types of functional proteins and each molecule of calmodulin has four spots for calcium binding.

3D structure of Ca2+-bound Calmodulin;Wikimedia commons;Public domain

Important cell mechanism: Excitation

Now we will talk about excitation. If the cell membrane becomes depolarized, this will make a regenerative electric response that we called action potential. This can often be seen in neurons and muscle cells. If you are wondering why this action potential is important, I will give you just one example. Creatures that have a big body can move faster because of this electric response in neurons and muscles.

Two processes can make action potential in their own interaction. Now it’s time to talk about other ions – potassium and sodium. The first process is a fast increase in permeability for sodium ions and the second one is a slower increase in permeability for potassium ions. The concentrations of sodium and potassium on the two sides of the membrane are not equal. Increase in permeability for sodium causes electric stream towards the inside of the cell, and in another side, high permeability for potassium ions causes electric stream towards the outside of the cell. Potassium and sodium channels were discovered 50 years ago, and after them, scientists discovered calcium channels, which are also important for generating the action potential, especially inside of heart or other smooth muscles.

Wikimedia commonsBruce BlausCC BY 3.0

Potassium channels are very important for cell functions. They have one of the main roles in different processes. Researches confirmed many different types of those channels and their importance for our body can be seen in the cases when a person has some kind of disorder in their function. For example, this can cause disorder in heart functions, neurological disorders and other. Even deafness or epilepsy can be caused by disorders in functions of potassium channels.

Wikimedia commonsPublic domain Potassium ions (purple) entering through potassium channel

We saw how the small pieces of our body can affect our whole organism. It is also important to say that many medicines are made to affect those spots in our body and to stop some disorders. Because of that, the researches in this area are really important.

Thanks for reading. I will appreciate your comments.

References:

Humphrey P. Rang, Maureen M. Dale, James M. Ritter, Philip K. Moore, Pharmacology, Novi Sad, 2005;

Bruce Alberts; Alexander Johnson; Julian Lewis; Martin Raff; Keith Roberts; Peter Walter, Molecular Biology of the Cell, New York: Garlard Science, 2012;

McDowall, Jennifer, "Calmodulin". InterPro Protein Archive.

Hodgkin AL, Huxley AF, "A quantitative description of membrane current and its application to conduction and excitation in nerve", The Journal of Physiology, 117 (4): 500–544, 1952.