All cells are surrounded by a barrier, or a membrane. The role of this membrane is to keep the internal content inside and the external content outside. However, the cell is not a balloon; some substances need to cross the membrane, including nutrients, minerals and waste. In order to allow passage of these substances every cell contains protein structures called membrane proteins that are in charge, among other things, of interactions with the extracellular environment, from signaling to transport. Among these proteins there is a very large family of proteins called ion channels. Ion channels are barrel-shaped hollow proteins that allow transport of ions (charged atoms like sodium, potassium and calcium) from one side of the membrane to the other, according to a gradient of concentrations. The movement of these ions is in fact a movement of charged particles, which is electrical current by definition. The ability to generate such a movement of particles, which relies on concentration gradients and the ability to cross the membrane) is called voltage, or potential. Ions are abundant on both sides of the membrane but in different concentrations. For instance: sodium and calcium are more abundant outside than inside, while potassium is more abundant inside than outside. The cell invests a considerable amount of energy to maintain this state.

When an ion channel opens, ions flow through it and change the balance of electric charges, thereby also changing the membrane potential. For example: when a sodium ion channel opens sodium ions flow from the outside to the inside of the cell, thereby increasing the number of positive charges inside the cell and increasing the membrane potential. This process is called depolarization. When a potassium ion channel opens, potassium ions flow from the inside to the outside,thereby decreasing the number of positive ions inside the cell reducing the membrane potential. This process is called hyperpolarization.

The opening and closure of ion channels is termed gating. Different ion channels have different gating mechanisms, among them physical stimuli, pH changes, binding of substances, voltage changes in the membrane and changes in temperature. Some of the ion channels are gated by changes in membrane potential. Some of them are activated by an increase in membrane potential and some by a decrease. When a nerve cell is activated, ion channels open and conduct sodium or calcium, thereby increasing the membrane potential. This increase causes voltage gated sodium channels to open. The membrane potential increases even further and then voltage gated potassium channels are activated, leading to a decrease in membrane potential. This causes a sort of an electric wave that travels through the membrane along the processes of the nerve cell (axons).This wave, also termed action potential, is the basic component of transmission of information in our nervous system. It is important to mention this, because the ion channels we'll be discussing next are initiators of such waves. For more information about the role of ion channels in generating the action potential watch the following video:

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Among the large group of ion channels there is a unique group of 28 members called Transient Receptor Potential ion channels or TRPs. Like many other proteins, this name was given for historical reasons by Prof. Baruch Minke about 36 years ago. TRP channels are gated by a wide variety of mechanisms such as mechanic pressure, chemical substances, signaling molecules, voltage and temperature. The three groups involved in temperature sensing are TRPM, TRPA and TRPV, where TRPV channels are involved in heat sensation and TRPM and TRPA in cold sensation.

TRPV is a family of 6 ion channels, four of which are involved in heat sensation (TRPV1-4) at different ranges covering a spectrum of temperatures from 27-52oC. Some of these ion channels are also activated by natural compounds such as capsaicin (active substance of chili peppers), allicin (active compound in garlic), ginger, cinnamon aldehyde, and allyl isothiocyanate (the active substance in mustard and wasabi). These ion channels are abundant mostly (but not only) in neuronal tissue in areas responsible for temperature sensing. When a TRPV channel is activated it stimulates the neuron and starts a signal going to the brain and conveying a "this is warm" or "this is hot" or "ouch, this is so hot it hurts" message. The effect of spicy compounds works in the same manner, implying that spiciness is not a taste but rather a sensation of heat or pain. TRPV1 blockage was shown to cause hyperthermia, showing its importance in body temperature regulation. Another interesting aspect of TRPV activation is the involvement of a negative feedback loop. Once TRPV is opened calcium flows in and triggers a chain reaction that culminates in inhibition of the channel. This is a mechanism meant to protect the cell from cell death due to high calcium levels.

You are probably wondering how temperature can affect the gating of an ion channel. Well, thermosensitive TRPs are also voltage sensitive. However, they are activated in voltages far above the physiological range, so in fact they are closed most of the time. What temperature does is it shifts the voltage sensitivity to the physiological range by making small changes in the membrane. This change leads to opening of the channel and thereby stimulation of the cell. The same mechanism applies for cold sensitive channels.

Homology model of the TRPV1 ion channel. This image was take from wikipedia.

Cold sensitive channels are TRPM8 and TRPA1. These ion channels work in a similar manner to TRPV channels, only they are sensitive to cold temperatures as well as to menthol and eucalyptol. Here there are no ranges, only "cold". The reason is actually quite simple. It is very important to be sensitive to different levels of warmth, while for low temperatures it is enough to differentiate between cool (TRPM8) and cold (TRPA1).

Regarding TRPM5 the story is quite different. TRPM5 is heat sensitive yet is also activated by receptors expressed in the sweet, bitter and umami (protein) taste buds. When tasting cold and hot chocolate, you will find the hot chocolate sweeter although the hot and cold chocolates are exactly the same. Since TRPM5 is heat sensitive and is activated by a sweetness receptor, hot chocolate will create a stronger taste signal originated by more open channels than cold chocolate.

TRP channels are also involved in pain sensation and inflammation, making them promising candidates for therapy; however one must bear in mind the effect of temperature sensitivity. For instance, a TRPV1 antagonist was tried during phase I clinical trials as a painkiller (TRPV1 is involved in pain sensation) and one of the side effects was an increase of 1.5oC in body temperature. Some TRPV channels (in altered forms) were found to be involved in several skeletal diseases. An interesting therapeutic approach for prostate cancer was based on pharmacological activation of TRPM8 and TRPV1 in attempt to flood the tumor cells with toxic levels of calcium.

These ion channels are studied by a unique technique called patch clamp, in which a special sharp tiny glass electrode is attached to a cell expressing the ion channel of interest. No matter if it’s a cell line or a freshly extracted neuron, in both cases investigators are able to measure channel activity down to a single channel. They are also able to manipulate its properties by changing membrane potential, adding stimulants, blockers or other modulators.

To summarize, we started by explaining what ion channels are and what is their role in transmission of information to the brain. We learned about two groups of temperature sensitive ion channels, and the mechanism of how they work. We learned why hot chocolate is sweeter then cold chocolate, and we learned how ion channels are studied. I would like to finish off by saying that although too many scientists think ion channels are "these holes in the membrane", the truth is actually that "the membrane is that oily thing between the ion channels".

Erez Garty
Department of Biological Chemistry
Weizmann Institute of Science
 

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