Hi Emily, thanks for the question. The answer is proteins. With exception of potassium ions, all ions (that pertain to membrane potential) have a higher concentration outside of the cell, than inside. However, nucleic acids are super negatively charged, and proteins tend to have a net negative charge, as well. Because those are large macromolcules that can't leave the cell, this pushes the membrane potential to around -70mV, with the inside being more negative than the outside.
Emily G.
asked 09/27/19At rest, the interior of a neuron is negatively charged relative to the exterior. The negative charge is due mainly to..?
- sodium ions
- chloride ions
- potassium ions
- proteins
I was thinking the answer is "2," but I am not positive.
3 Answers By Expert Tutors

Michael S. answered 09/28/19
Medical Student with Extensive Tutoring Experience
Hi Emily! That's a tricky question. First, let's talk about the physiology that is being tested, then we'll take a look at that question.
The negative charge of the interior of a neuron relative to the exterior is known as "resting potential," and it's driven by a few processes that, acting together, produce that relative charge of about -70 mV.
You can see the 3 major processes here:
https://en.wikipedia.org/wiki/Resting_potential#/media/File:Sodium-potassium_pump_and_diffusion.png
The first (channel on the left in the picture linked above) is passive efflux of K+ through leak channels. The intracellular space has a much higher [K+] than the extracellular space (about 150 mM v. 5 mM) so K+ will go down its concentration gradient and leave the cell.
The second (center channel) is an active transport process, meaning it requires ATP. This transporter is the Na/K ATPase pump and it pumps 3 Na+ out and 2 K+ in, using ATP to drive these ions against their concentration gradients. This is the major force contributing to the resting membrane potential, and it's how we wind up with so much K+ inside a cell and so much Na+ outside.
Lastly, Na+ influx (via the channel on the right) is a passive diffusion process that allows Na+ to flow down its concentration gradient into the cell, because the outside of the cell has far more Na+ than the intracellular space (140 mM v. 10 mM).
However, the question seems to be asking more about how the presence of these molecules is driving the charge. Let's go through those one-by-one:
Na+ is positively charged, and it is found in much higher concentrations outside the cell (140 mM) than inside the cell (10 mM). Therefore, this would make the intracellular space less positive than the extracellular space, so this is an option.
Cl- is negatively charged, but it is found in much higher concentrations outside the cell (105 mM) than inside the cell (7 mM). Therefore, this would actually make the intracellular space less negative than the extracellular space, so this is likely not the correct answer.
K+ is positively charged, but it is found in much higher concentrations inside the cell (150 mM) than outside the cell (5 mM). Therefore, this would actually make the intracellular space more positive than the extracellular space, so this is likely not the answer.
Proteins are usually considered to have a negative charge, and they are found in very high concentrations in the intracellular space (155 mM). This would make the intracellular space more negative than the extracellular space, so this is an option.
So we've narrowed it down to 1 and 4, and we have to decide whether the distribution of sodium ions or the the distribution of proteins better explains the negative charge within the cell.
While both of these molecules contribute to the negative resting membrane potential, the negative charge within the cell is driven primarily by the Na/K ATPase pump, which establishes these electrochemical gradients. It's true that there is a lot of protein in the intracellular space, but that's not something the cell will pump across it's membrane to modify the electrical potential of the cell. Instead, that comes from the Na/K ATPase pump, which is the main determinant of the resting potential. That's why, if I was answering this question, I would probably choose 1. That said, the question is a little unclear (for example, I'm not sure if it's referring to the instantaneous concentrations - which is what I assumed in the explanation above - or the transport, which would change the answer, because it's the efflux of potassium that moves a positive charge out of the cell and decreases the membrane potential).
If you'd like to read more about resting potentials and electrochemical gradients, you can check out a great article about membrane potentials on Khan Academy called "The Membrane Potential: how resting membrane potential is established in a neuron." https://www.khanacademy.org/science/biology/human-biology/neuron-nervous-system/a/the-membrane-potential
I hope this helps! Let me know if you have any lingering questions
Brian M. answered 09/27/19
PhD in biology. 2 years teaching experience, 10+ years tutoring
It's ironic that you're not "positive".
I'm happy to explain action potentials to you if you'd like.
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