It is useful to consider the formation of the neuron resting potential in imaginary steps, but in reality they occur simultaneously. Imagine a neuron with no membrane potential and no concentration gradients for organic anions, potassium, sodium, chloride, or calcium. As the neuron creates and adds organic anions to the cytoplasm, their negative charges would cause a small membrane potential, perhaps around -5 mV. This would probably be insufficient for the neuron to function. Electrical and diffusion forces would both try to drive the organic anions out of the neuron, but because the membrane is highly impermeable to them no further change would occur. The other ions are able to cross the membrane through passive transport channels called leak, or leakage, channels, although the degree of membrane permeability through these channels varies between the ions.
Now consider what happens if the sodium-potassium pump is added to the membrane. It will use the energy contained in one adenosine triphosphate molecule to actively transport three sodium ions outside the neuron and two potassium ions inside the neuron. By pumping more cations outside than inside, the membrane potential would further increase in size by a small amount, so that it might now be something like -10 mV, but it would still be at some small size that would probably be insufficient for the neuron to function. More importantly, however, the pump creates concentration gradients for sodium and potassium by decreasing the intracellular concentration of sodium and increasing the intracellular concentration of potassium. The extracellular fluid volume and the total number of ions outside the neuron are both huge compared to the intracellular volume and the total number of ions inside the neuron, so that any change to extracellular ion concentrations is negligible. This will be true for any movement of ions across the cell membrane during any activity of neurons discussed below.
There are now opposing forces on potassium: the electrical force is trying to drive it into the cell, while the diffusion force is trying to drive it out of the cell. At typical neuron ion concentrations, the diffusion force would be stronger than the electrical force at this step, so that the net electrochemical driving force (the larger diffusion force minus the smaller electrical force) would cause a net outward flow of potassium through the leak channels. As the positive charge of each potassium ion exits the cell, the membrane potential grows larger until it is large enough that the electrical force driving potassium into the neuron is equal in size to the diffusion force driving potassium out of the neuron, at which point the net movement of potassium across the membrane stops. This membrane potential is called the equilibrium, or reversal, potential of potassium, which, at typical neuron ion concentrations, is around -70 mV. This membrane potential would be more than enough for the neuron to function. Less than 1% of 1% of all the potassium ions inside the neuron need to exit to reach the equilibrium potential, so that the effect on the intracellular concentration of potassium is negligible. This process takes some time, however, because most of the membrane is impermeable to potassium, which has to squeeze through the leak channels to cross.
Both the electrical and diffusion forces are strongly trying to drive sodium into the neuron. If the membrane was only permeable to sodium, these cations would flow into the neuron until the membrane potential reached the equilibrium potential of sodium, which, at typical neuron ion concentrations, is around +50 mV. Without input, however, the resting neuron membrane permeability of sodium through the leak channels is much less than that of potassium, at around 4%. So that at this imaginary step the membrane potential might settle in at around -60 mV, which is a common neuron resting potential. When the membrane is permeable to multiple ions with electrochemical driving forces, the resulting membrane potential is a weighted average of the equilibrium potential of these ions, weighted by their permeability. At rest, the neuron membrane is more permeable to potassium than sodium, so the resting potential is closer to the equilibrium potential of potassium than that of sodium. Because the concentrations and permeabilities of ions are usually stable in most resting neurons, the resting potential is usually stable as well. Now neither potassium nor sodium is at its equilibrium potential, however, so that there will be a small amount of net movement of both ions across the membrane. This will be matched by ongoing activity of the sodium-potassium pump to maintain the concentration gradients.
The resting membrane usually has an intermediate permeability to chloride, of around 45% compared to that of potassium. In contrast to potassium and sodium, where their concentration gradients mostly drive changes to the membrane potential, for chloride the electrical force from the membrane potential mostly drives formation of its concentration gradient. The membrane potential drives chloride out of the neuron until its diffusion force is large enough to balance the electrical force. The equilibrium potential of chloride, therefore, is usually near the resting potential of around -60 mV. Most neurons also have other active means of decreasing the intracellular concentration of chloride, the main one being the chloride-potassium symporter, which uses the diffusion force acting on potassium to drive chloride out of the neuron in exchange for allowing potassium to exit. Because of this, the equilibrium potential of chloride for most neurons is usually not at the resting potential of around -60 mV, but instead it is around -70 mV, which will cause some inward chloride flow leading to a minor change to the resting potential to a more negative value, although this is usually negligible.
Most neurons also have active means of decreasing the intracellular concentration of calcium, the main one being the sodium-calcium exchanger, which uses the electrical and diffusion forces acting on sodium to drive calcium out of the neuron in exchange for allowing sodium to enter. The equilibrium potential of calcium is therefore around +120 mV, but because the membrane permeability for calcium tends to be small it usually has little effect on the resting potential. While the concentration gradients of chloride and calcium tend to have little effect on the resting potential of most neurons, they play major roles in other aspects of neuron function discussed below.