Sodium Channels and Pain Genetics

Pain is in the brain, or at least the perception of pain occurs in the brain. But actually, what you perceive as pain is the result of a series of chemical and electrical impulses that originates with a special type of receptor, called a nociceptor (sometimes just called a pain receptor).  Nociceptors detect the chemical signals that cells produce when they are damaged, for example by a burn. When these stimuli overcome a threshold level, the nociceptor sends a signal to the brain, which integrates it with other information and, if needed, develops the sensation of pain.

As for most things in the worlds of genetics and medicine, we get hints as to how a system functions by looking at what happens with something goes wrong. Such is the case with pain. Pain is a difficult thing to quantify. If you have ever been to a hospital and the nurse asks you to describe your pain from a 1 to a 10, then you know you know the confusion of distinguishing between a level 4 and level 5 pain. However, there is a rare condition called congenital analgesia,  in which individuals can not sense pain.  People with congenital analgesia often break bones and experience severe burns due to an inability to tell when their tissues are being damaged.  By studying congenital analgesia researchers can examine what happens when a sensory system fails completely.  These types of studies have determined that the condition is caused by mutations in the genes that form the sodium channels in the nociceptors.

But before we get into the genetics of congenital analgesia, let’s first take a look at sodium channels in general. Basically, sodium channels (and their close allies – potassium channels)  form regions through a cell membrane that allow for the rapid diffusion of ions from areas of high concentration to low. Here is our video on how these channels (and the sodium-potassium pump) work:


Channel Proteins from Ricochet Science on Vimeo.

The sudden rush of positively-charged sodium ions creates an electrical spike across the membrane. If the channel is in the membrane of a neuron, then this temporary spike is called an action potential (or nerve impulse). This is what is responsible for relaying information along the neurons of your nervous system. While the action potential itself is an “all-or-nothing” event, there is some variation not only in the thresholds that cause the channels to open, but also how fast the channels allow the movement of the ions.

So now for a little bit of pain genetics. In individuals with congenital analgesia, the gene that accounts for one of the three types of sodium channel is mutated. Sodium channels are an example of a protein with quaternary structure, meaning that there are multiple subunits in the protein. Mutations in any of the genes that produce the subunits can cause problems with the function of the channel protein.

One of the first genes to be identified was SCN9A, a gene located on chromosome 2 (2q24). There are a number of possible mutations in SCN9A (over 13 have been identified). If the mutation causes the channel to fail completely (no sodium ion movement), then the individual experiences no pain. But if the mutation causes the channel to be overactive, then the person experiences almost constant pain.

A new mutation has been discovered that does almost exactly the opposite. Called SCN11A (chromosome location 3p22.2), this gene encodes for another of the sodium channel subunits. However, this time the new mutation causes the channel to be hyperactive, and in doing so prevents a charge from being developed across the membrane. This, in turn, prevents a pain signal from being sent to the brain. The researchers (at Jena University Hospital ) who identified the mutation propose that it may be a form of gatekeeper gene whose function is to prevent the neuron from firing rapidly.

There has been some hope that understanding these mutations may promote the development of new drugs to alleviate pain. However, the problem with developing a drug that targets the action of sodium channels is that these proteins are so common throughout the body. In fact, every cell of the body possesses some sodium channels. For example, the action of the kidneys and the generation of the heartbeat both rely upon sodium channels. So, at least for now, simply turning them off is probably not an option for new medications.

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Authors note: Updated on December 8, 2013 with new references – mw

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