Resting membrane potential is determined primarily by two factors: the unequal distribution of ions across the cell membrane and the membrane’s selective permeability to those ions. In a typical neuron, this produces a voltage of about -70 to -80 millivolts (mV), meaning the inside of the cell is electrically negative compared to the outside. Understanding how this voltage arises requires looking at the specific ions involved, the channels that let them pass, and the pumps that maintain the whole system.
Ion Concentration Gradients Set the Stage
The most important ions for resting membrane potential are potassium (K+), sodium (Na+), and chloride (Cl-). These ions are distributed unevenly between the inside and outside of the cell, and that imbalance is the raw material for creating voltage.
In a typical mammalian neuron, potassium is heavily concentrated inside the cell at around 125 to 140 millimolar (mM), while the outside fluid contains only about 5 mM. Sodium shows the opposite pattern: roughly 145 mM outside and only 5 to 15 mM inside. Chloride sits at about 150 mM outside and 13 mM inside. These concentration differences mean that each ion has a natural tendency to flow in a specific direction. Potassium wants to leave the cell, sodium wants to enter, and chloride wants to enter.
If you could calculate the voltage needed to perfectly balance each ion’s tendency to move down its concentration gradient, you’d get what’s called the equilibrium potential for that ion. For potassium, this value is approximately -85 mV. For sodium, it’s about +60 mV. For chloride, it’s around -65 mV. These numbers represent the voltage the membrane would settle at if it were permeable to only that one ion. The actual resting membrane potential falls somewhere between these values, weighted by how easily each ion can cross the membrane.
Potassium Permeability Dominates at Rest
The cell membrane isn’t equally permeable to all ions. At rest, it is far more permeable to potassium than to sodium or chloride, and this single fact is the biggest reason the resting potential is negative.
This high potassium permeability comes from leak channels: ion channels that stay open all the time, regardless of voltage or chemical signals. The most important of these belong to a family called two-pore domain potassium (K2P) channels. These channels generate steady “leak” currents that allow potassium to flow out of the cell down its concentration gradient. Because potassium carries a positive charge, its departure leaves the cell interior more negative.
The membrane does allow a small amount of sodium to leak in, which pulls the voltage slightly in the positive direction. This is why the resting potential of a neuron (around -73 mV) is not quite as negative as potassium’s equilibrium potential (-85 mV), but is far from sodium’s equilibrium potential (+60 mV). The resting potential sits much closer to the potassium value because potassium permeability is so much greater than sodium permeability at rest.
Trapped Negative Molecules Inside the Cell
The inside of a cell contains large negatively charged molecules, mostly proteins and phosphate compounds, that are too big to cross the membrane. These fixed negative charges contribute to the overall negative interior of the cell. They don’t fluctuate the way ion concentrations do, but they create a baseline negative environment that influences how ions distribute themselves. Think of them as a permanent negative backdrop that helps hold the resting potential in negative territory.
The Sodium-Potassium Pump Maintains the Gradients
Left unchecked, the small but constant leak of potassium out and sodium in would eventually run down the concentration gradients, and the resting potential would collapse. The sodium-potassium pump prevents this. It uses energy (in the form of ATP) to push three sodium ions out of the cell for every two potassium ions it brings in, continuously restoring the concentration differences that the leak channels slowly erode.
Because the pump moves three positive charges out for every two it brings in, it has a small direct electrical effect, making the inside of the cell slightly more negative than it would be from ion gradients alone. This direct contribution is modest, typically a few millivolts. The pump’s far more important role is indirect: by maintaining the steep potassium and sodium gradients, it sustains the conditions that allow the resting potential to exist in the first place. Without the pump, a cell would gradually depolarize and lose its ability to generate electrical signals.
How the GHK Equation Ties It Together
Scientists use a formula called the Goldman-Hodgkin-Katz (GHK) voltage equation to calculate resting membrane potential. Rather than looking at one ion at a time, this equation accounts for all the major ions simultaneously. It takes three inputs for each ion: its concentration inside the cell, its concentration outside the cell, and the membrane’s permeability to that ion.
The equation essentially performs a weighted average. Ions with higher permeability have more influence on the final voltage. Since potassium permeability dwarfs sodium permeability at rest, potassium dominates the calculation, pulling the result toward -85 mV. The small sodium permeability nudges it back toward the positive direction, and the final answer lands near -73 mV for a typical neuron. If you changed any of the inputs, the concentration of an ion or the membrane’s permeability to it, the resting potential would shift.
Why Resting Potential Varies by Cell Type
Not all cells have the same resting membrane potential. Neurons typically rest around -70 to -80 mV, while skeletal muscle cells sit near -90 mV and cardiac muscle cells also rest around -90 mV. The differences come down to the same factors: each cell type has its own mix of ion channel types and densities, which creates a unique permeability profile. A cell with more potassium leak channels relative to sodium channels will have a more negative resting potential. A cell with slightly higher sodium permeability will rest at a less negative voltage.
What Happens When Potassium Levels Change
One of the most clinically relevant demonstrations of how resting potential works involves changes in blood potassium levels. Normally, the large difference between intracellular potassium (around 140 mM) and extracellular potassium (around 5 mM) helps maintain a strongly negative resting potential. When extracellular potassium rises, a condition called hyperkalemia, that gradient shrinks.
With a smaller gradient, less potassium flows out of the cell, and the resting potential becomes less negative. A cardiac muscle cell might shift from -90 mV to -80 mV. This might sound like a small change, but it has real consequences. The gap between the resting potential and the threshold for firing (the voltage at which the cell generates an electrical impulse) narrows. In mild hyperkalemia, this makes cells more excitable, easier to trigger. As potassium levels climb higher, however, the resting potential becomes so depolarized that the cell can no longer fire properly, leading to dangerous slowing of electrical signals in the heart.
This example illustrates a core principle: resting membrane potential is not a fixed property of a cell but a dynamic value that depends on ion concentrations and membrane permeability. Anything that alters either factor, whether disease, medication, or metabolic changes, will shift the resting potential and change how the cell behaves electrically.