Across the cell membrane of each neurone there exists a small difference in electrical charge, known as the membrane potential. In electrically inactive neurones, this is known as the resting membrane potential. Its typical value lies between -50 and -75 mV.
In this article, we will explore how the resting membrane potential is generated, how to calculate its approximate value and how changes in resting membrane potential may lead to significant pathology.
In overview, the resting membrane potential arises due to the differences in concentration gradient and electrochemical gradient across the cell membrane. Sodium (Na+) and chloride (Cl–) ions are present in greater concentrations extracellularly than intracellularly, whereas potassium (K+) ions are present in greater concentrations intracellularly than extracellularly.
Additionally, there are organic anions; these negatively charged molecules are most prevalent intracellularly.
The Na/K ATP-ase pump plays an essential role in maintaining the sodium and potassium concentrations by actively transporting these ions against their concentration gradients. Three sodium ions exit the cell in return for two potassium ions.
Overall, the intracellular environment is negatively charged compared to the extracellular environment, hence the resting potential of ~-50 to -75mV. If the membrane potential becomes more positive than the resting potential, the membrane is said to be depolarised, and if it becomes more negative than the resting potential the membrane is said to be hyperpolarised.
The rest of the article will explore the above concepts in more detail.
The Cell Membrane
The cell membrane acts as a selective filter, allowing the free movement of some molecules across it while tightly controlling the movement of others. Passage of a specific substance across the membrane depends on multiple factors including its electric charge, molar mass and the polarity of the molecule.
Movement of uncharged substances, like O2, CO2, urea, alcohol and glucose, depends only on their concentration gradient. The cell membrane is permeable to these molecules, and so they can move freely as their concentration gradients allow.
Charged substances such as K+, Na+, Cl– ions, cannot easily diffuse through the cell membrane due to its internal hydrophobic structure. Hence, to cross the cell membrane charged substances will utilise specialised, water-filled pores known as ion channels.
There are multiple types of ion channels depending on the type of ion that they are conducting. Importantly, ion channels are selective for a particular ion or ions.
There are three factors that can induce the movement of the ions through ion channels:
- The concentration gradient – a difference in concentration of the ion on the two sides of the membrane. Ions would cross the membrane from a compartment with a higher concentration to the compartment with a lower concentration.
- The electrical gradient – an electrical potential difference across the membrane defined as the electrical potential value inside the cell relative to the extracellular environment. Positive ions will be attracted to negative electrical potential and repelled from positive electric potential, and vice versa.
- Active Transport.
To better understand how the concentration gradient and the electrical gradient influence the movement of ions across the cellular membrane, let’s analyse the movements of potassium (K+) ions:
- The concentration gradient – The intracellular concentration of potassium greatly exceeds the extracellular concentration (~130mmol/L vs ~4mmol/L). Thus, potassium ions will tend to exit the cell according to the concentration gradient.
- The electrical gradient – As positively charged K+ ions are released, the charge of the intracellular space becomes relatively negative. Hence, some K+ ions are attracted back towards the intracellular space, despite the concentration gradient leading them in the opposite direction.
Thus, two “streams” containing K+ ions are created; one that expels potassium as per its concentration gradient, and one which attracts potassium as per the increasing negative intracellular electrical environment.
At the equilibrium potential, the rate at which ions leave by concentration gradient is equal to the rate at which ions enter via the electrochemical gradient.
Importantly, in a cell where only one type of ion can cross the membrane, the resting membrane potential will equal the equilibrium potential for that particular ion.
The Nernst equation is used to calculate the value of the equilibrium potential of a particular cell for a particular ion:
where Vm = equilibrium potential for any ion [V]; z = valence of the ion, [C]0 = concentration of ion X outside of the cell [mol]; [C]i = concentration of ion X inside the cell [mol].
So, assuming only potassium ions could cross the membrane and knowing common values for the intracellular and extracellular concentrations of potassium, one can calculate the approximate resting potential of a cell. In the example below, K0=4 and Ki=126 are used as common values:
Resting Membrane Potential Generation
While the Nernst equation for potassium provides a good approximation, the calculation of resting membrane potential is slightly more complicated because it is not the only ion involved.
Alongside the flux of potassium ions towards the extracellular space, sodium, chloride and other ions also cross the membrane. For example, the positively charged sodium ions enter the neurones down the concentration gradient but they are also attracted by a negative electrical potential inside the neurone.
Hence, this movement will make the resting potential less negative. Overall, the resting potential accounts for the movements of all ions across the membrane.
The table below summarises the main direction of movement for various ions and the overall impact this has on the resting membrane potential of a neurone:
|Ion||Overall direction of movement||Overall impact on resting potential|
|Potassium||Extracellular||Makes it more negative|
|Sodium||Intracellular||Makes it more positive|
|Chloride||Intracellular||Makes it more negative (small impact)|
|Organic anions||Cannot cross the membrane||Makes it more negative (small impact)|
Whilst all of these contribute to the resting membrane potential, the cell is most permeable to sodium and potassium ions and so these will have the greatest impact. As the cell membrane of neurones are most permeable to potassium, the resting membrane potential will be closest to the equilibrium potential for potassium ions, with the impact of sodium ion influx making it slightly less negative (i.e. -75mV as opposed to -92mV).
If there was to be any change in the permeability of the cell membrane to ions (via channels opening or closing) then the membrane potential would be altered – this is how action potentials are generated.
Maintaining the Resting Membrane Potential
Without something to maintain the ionic concentration gradients, the resting membrane potential would dissipate, and so therefore would the membrane potential. The sodium-potassium pump (Na+ K+ ATPase) prevent this and maintains the ionic differences across the membrane.
This pump actively transports potassium and sodium ions against their electrochemical gradients (i.e. potassium moves intracellularly and sodium moves extracellularly). This allows the concentration gradient that these ions travel down to be maintained and therefore, for the resting membrane potential to be maintained.
Clinical Relevance – Hyperkalaemia
Hyperkalaemia is the medical term that describes a potassium (K+) level in the blood that is higher than normal. The normal blood potassium level is normally 3.6 to 5.2 millimoles per litre (mmol/L).
In the setting of hyperkalaemia, the resting membrane potential is shifted to a less negative value as the concentration gradient driving the movement of K+ ions out of the cell is reduced. So, a normal resting potential value of −70 mV is altered to a less-negative value. This change moves the resting membrane potential closer to the threshold for action potential generation.
Thus, the neurone enters into a state of heightened excitability, so smaller deviations from this new resting potential are needed to promote action potential generation. Hence, hyperkalaemia may significantly interfere with the physiological functions of nerve cells or muscles. For example, it is known to induce dangerous arrhythmias.