By Chris Jung
Although our body’s cells often get a lot of attention in biology class, the space between them is almost nearly as important - the electrochemical balance must be kept in peak condition for our cells to function properly, and plays an especially important role in communication.
Ionic movements dictate many of our body’s physiological functions - from the pumping of our heart to the signaling in our neurons. And the fundamental chemistry of these ion movements is surprisingly simple compared to the rigor of the biochemical field: it is due to the same process of “opposites attract” that you learned in elementary school.
Ions can be positive or negative (think: Na+, Ca2+, K+, Cl-, Mg2+), and it is these charges that create an electric current in our cells. To really understand what is happening in our cells, we have to go back to some pretty basic biochemistry.
A concentration gradient occurs when the concentration of particles is higher in one area than another. According to the second law of thermodynamics, everything in the universe wants to reach a point of equilibrium. So when there are more particles in one side of a cell than another, a concentration gradient is formed because the particles are not at equilibrium - ideally, there would be an equal number of particles on both sides.
Diffusion is when particles move down their concentration gradients to reach a point of equilibrium (when the number of particles is equal). In our cells, this process is naturally occurring and it is called passive transport (passive because it requires no energy). And although this seems like a fundamental rule that you learn in class, there is an obvious mathematical reason why this happens that is often overlooked in biology class - the intuitive principles of Einstein’s famous Brownian motion tell us the more particles there are in a fluid, the more collisions and the particles will eventually spread out to areas with lower collisions (even ions get bored of an endless ride of bumper cars).
Small and uncharged particles, such as gases, can simply move down their concentration gradients and diffuse across cell membranes. But unfortunately, ions can’t cross through the cell membrane; it is a phospholipid bilayer (the neutral hydrophobic fatty layer really doesn’t like charged particles - exactly why water and oil don’t mix).
Instead, ions need to pass through “doors”: these doors are protein channels: typically made of ~4 transmembrane proteins that open and close. Protein channels are specific to different ions and will only let certain ions through!
Diffusion through these protein channels is called facilitated diffusion: ions will pass as long as the proteins are open, and it is still passive transport, requiring no energy.
So if these channels open, they will let ions move down their concentration gradients, to try to balance their number on each side. For example, a channel may allow K+ to move from the inside of a cell—which has a high concentration of K+ ions—to the outside of the cell, which has an extremely low concentration (because of the tireless work of the Na-K+ ATPase pump). Sounds fairly simple - but then why don’t all of the ions just move down their channels and remain at equilibrium?
Well, for one thing, there’s the aforementioned ATPase pumps and active transport mechanisms forcefully pumping ions against their concentration gradients to create difference in charge. But the main reason behind this imbalance of charge is due to something called a membrane potential.
Inside the cell, cations “get together” with anions because opposites attract (even ions hate being single). When the cations leave the anions by diffusing through protein channels, the anions get lonely, and they create a negative charge (the ion equivalent of an “I miss you and I’m lonely without you” text). Then the cations, which are outside of the cell, want to get back in the cell because of this negative charge (in this example the cations left the cell - the most common example being K+ - but anions can leave and the roles would simply be reversed).
The main point here is that there is one “force”, the concentration gradient, that is driving ions out, but there is another force, the membrane potential, that attracts these ions back inside. This can be calculated using the Nernst equation for single ions.
The ions leak out of the channels until a certain point when the ions will sense a negative charge coming from the anions and reenter the cells. This cycle repeats until the charge of the cell has reached its equilibrium potential; that is, when the force of electrical potential energy (the membrane potential) matches the force of the concentration gradient. If the concentration gradient is higher (there are a lot more ions on one side), then the equilibrium potential will have to be higher to balance it out!
But real cells are permeable to multiple ions. Potassium, sodium, chloride, and calcium are some of the many ions that can leave and enter a cell. These four ions contribute to the majority of the resting potential of a cell. To truly calculate the membrane potential, you must factor in each ion and how many times it passes the cell membrane—that is, how permeable the membrane is to certain ions (equilibrium for multiple ions can be calculated using the more precise Goldman Hodgkin-Katz equation, which is derived from the Nernst - note the same constant RT/F).
Let’s put this all together: each cell has a resting membrane potential based on their permeability to certain ions. A process called depolarization occurs when the membrane potential becomes more positive because of the opening of ion channels. For example, if a lot of Na+ suddenly came into a cell because proteins permeable to Na+ opened, then the cell would be more positive and would depolarize. Hyperpolarization is the opposite: it’s when membrane potentials become more negative. For example, if Chloride (Cl-) ions came into a cell, then the cell would be more negative. But all cells will return to equilibrium because of the “push-and-pull” forces of concentration gradients and membrane potential, reaching its resting membrane potential!
In physiology, an action potential is defined as when the membrane potential of a cell location rapidly depolarizes and repolarizes: this rapid depolarization passes to other cells (the exact method for this is specific to the cell), creating an electrical current that can be measured by devices such as an EKG (electrocardiograph) or EEG (electroencephalograph).
With our newfound understanding of membrane potentials and the electrochemistry of cells, we can now begin to apply this to the biological processes in certain cells such as our heart’s pacemakers and cardiac myocytes, our muscle cells (myocytes), and neurons! Here, we will focus specifically on neurons in line with the application to LTP. The resting membrane potential for neurons is -70 mV: essentially, 70 mV of electrical potential energy is required to balance the concentration gradients of all the ions in a typical neuron (negative because the main permeable ions are concentrated inside the cell).
Neurotransmission is the transmission of action potentials between neurons, but it is not as simple as just passing ions through cell junctions (which is how transmission works in the heart). There are a few key terms you need to know to understand the process of neurotransmission:
The point of communication between two neurons is called a synapse, but the neurons aren’t actually touching. In very tiny gaps called synaptic clefts (~20 nm), they pass on signals. All of the three main sections of a neuron - the soma (cell body), the dendrites (receive the signal), and axons (send the signal) - are involved in neurotransmission.
The neuron that fires, and sends the signal across the synapse, is called the presynaptic neuron. Postsynaptic neurons are the receiving neurons of the synapse.
Here’s the catch: ions can’t pass across these synapses. Instead, neurotransmitters are exocytosed from the presynaptic neuron’s axon terminal as the “messengers” to carry on the signal. Neurotransmitters are very diverse: common neurotransmitters include small peptides, gases, monoamines, and purines. Peptide neurotransmitters must be synthesized in the cell body.
Neurotransmitters bind to receptors on the membrane of post-synaptic neuron’s dendrites: some of these receptors are ionotropic, while some are G-protein linked. Excitatory neurons “excite”, or depolarize, their neighbors - 80% of these neurons use the neurotransmitter glutamate to depolarize the next cell. Other common excitatory neurotransmitters are acetylcholine, dopamine, adrenaline, and histamine.
Inhibitory neurons “dull” the signal by hyperpolarizing the next cells, inhibiting the signal from passing through, as the postsynaptic cell becomes more negative. This is achieved through inhibitory neurotransmitters, the most common one being GABA (Gamma-aminobutyric acid).
After these neurotransmitters bind, the receptors open and let in ions, which either hyperpolarize or depolarize the next cell. Through a process called “reuptake”, these neurotransmitters are “recycled” - endocytosed back into the presynaptic neuron’s axon terminal for future use. Recent research has revealed that astrocytes may play a significant role in neurotransmitter reuptake, influencing the strength of connections between the neurons by influencing the duration that the receptor remains open.
Whew! That was a mouthful! Hopefully, by now you can see the intricacies of one of the most basic concepts of physiology - membrane potentials are often blown off as being elementary but they are quite a nice representation of the interrelation of chemistry, physics, biology, and even aspects of quantum mechanics (if you really want to dive into the Brownian motion).
Every single signal in your brain forming your thoughts goes through the process of neurotransmission thousands of times every second! A slight “glitch” in any of these processes has vast implications in the pathology of psychiatric, neurodegenerative, and psychological disorders - there is an endless amount of research that could be done! For now, pat yourself on the back for learning about one of the fundamental concepts of physiology and admire the incredible processes that your body undergoes while maintaining homeostasis.
Citations:
Henneberger, C., Papouin, T., Oliet, S. H., & Rusakov, D. A. (2010). Long-term potentiation depends on release of D-serine from astrocytes. Nature, 463(7278), 232–236. https://doi.org/10.1038/nature08673
Namiki, Mikio. “Quantum Mechanics and Brownian Motions.” Recent Developments in Infinite-Dimensional Analysis and Quantum Probability, 2001, pp. 275–282., doi:10.1007/978-94-010-0842-6_19.
Yang, Y., et al. “Contribution of Astrocytes to Hippocampal Long-Term Potentiation through Release of D-Serine.” Proceedings of the National Academy of Sciences, vol. 100, no. 25, 2003, pp. 15194–15199., doi:10.1073/pnas.2431073100.