I’ve been wanting to write this article since February 28th when Jan Kucera from the University of Bern gave a webinar on cardiac ephaptic coupling as part of the Worldwide Sodium Channel Seminars.
You know, there’s something strange to me about the term “ephaptic coupling.” I’m a big fan of simplicity, and this term is anything but simple. Seriously, if you’ve never heard of ephaptic coupling before, just take a pause and try to guess what it means.
I did a small experiment where I asked several non-scientists in my circle what they think I’m talking about when I say “ephaptic coupling.” Maybe it was the way I pronounced it, but they all told me it sounded like I was swearing. It’s like when you’re trying to do something and it doesn’t work, and in frustration, you exclaim: “Ephaptic coupling!”
Although I found this situation amusing, I don’t think it’s fair. People deserve to know the truth about ephaptic coupling, especially considering that this phenomenon is intimately connected with ion channels and even has a little bit of magic in it.
So, here it is. The truth.
The word “ephaptic” comes from the Greek word “epi” which means “upon”, and “haptikos” which means “touching”. Therefore, “ephaptic” signifies the act of touching, and ephaptic coupling refers to the special type of communication between adjacent excitable cells, such as neurons or cardiomyocytes.
When we talk about communication between neurons, for example, most of the time, we are talking about chemical or electrical synapses. At a chemical synapse, communication is mediated by chemicals-neurotransmitters that are sent from one neuron to another. At an electrical synapse, two neurons or cardiomyocytes are physically connected by gap junctions – specialized intercellular channels that allow different ions to flow directly from one cell to another.
Ephaptic coupling represents yet another way of communication that is not mediated by chemicals or physical connections. Rather, it is mediated by extracellular electrical fields.
Let me explain. When a neuron or a cardiomyocyte fires an action potential, it generates an extracellular signal (electrical field). We can detect this signal with an extracellular electrode. And although these signals are rather small and highly localized, sometimes they are big enough for one cell to affect adjacent cells and make them more or less likely to fire their own action potentials. Simply put, a cell can influence the electrical excitability of adjacent cells without any physical contact or chemical transmission. This is called ephaptic coupling.
For ephaptic coupling to be effective, the distance between adjacent cells must be very small, and also, the ion channel density in areas of close proximity must be high. For example, in cardiomyocytes, ephaptic coupling occurs in the narrow (~10nm) intercellular clefts of intercalated discs and relies on the presence of high-density Nav1.5 channel clusters adjacent to the gap junctions.
Despite skepticism regarding the actual effects of ephaptic coupling, recent research suggests that it plays a crucial role in both physiological and pathological conditions.
You know that in the heart, for example, gap junctional coupling is usually considered to be the primary mechanism for action potential propagation. Gap junctions in the intercalated discs of cardiomyocytes allow ions to flow freely between adjacent cells and synchronize their activity. However, accumulated evidence suggests that ephaptic coupling between cardiomyocytes may also contribute to the synchronization of their electrical activity and the overall function of the heart. In fact, ephaptic coupling is now seen as a mechanism that helps sustain cardiac conduction during pathologies, when gap junctional coupling is compromised. Therefore, it is now considered a target for antiarrhythmic therapies.
In the brain, ephaptic coupling has been shown to influence the synchronization and timing of action potential firing in neurons. Therefore, it is now regarded as a potential mechanism that contributes to epileptic synchronization. It has been demonstrated that by simply reducing the space between cells in hippocampal slices, the frequency of occurrence of epileptiform dynamics increases, even in the absence of any synaptic or gap junction coupling.
One of the most “shocking” experiments regarding ephaptic coupling was conducted by Chiang et al. in 2019 (here). The authors studied slow periodic activity in murine hippocampal slices and demonstrated that this activity could propagate across the slice without synaptic transmission. They then cut the slice into two separate pieces and placed them in close proximity with a clear gap between them. Astonishingly, slow periodic activity continued to propagate from one piece of the slice to another, demonstrating ephaptic coupling in action.
You know, when we talk about ion channels, we love to tell that we all are electrical beings. It’s fascinating to think that ion channels make us electrical. But ion channels appeared to be even more remarkable than I previously thought. Ion channels perform real magic by enabling cells to control other cells from a distance, much like magicians who move objects on the stage without physical contact.