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Membrane potentials, action potentials, and neurons

By Sgt York in Science
Sun Oct 24, 2004 at 11:48:57 AM EST
Tags: Science (all tags)

Neural impulses, synaptic transmission, and drug action : A 3 part series

Part I : Membrane potentials and action potentials

Part II : Synaptic transmission, some neurophysiology

Part III: Action of selected drugs

How does cocaine work? How about THC? Amphetamines? X? Ketamine? How does Alzheimer's cause memory loss? Why do people with Parkinson's get the shakes? What is pain? What are the endorphins, and how do they work? Some of these questions have been worked out, some are still inder investigation, and some are the topic of heated debate in the scientific community. The mechanism of drug action has historically been a controversial field, filled with misconceptions in the eyes of the public as theories change with the introduction of new data, new mechanisms, and even new molecules. Here, we will begin to explore some of the concepts behind these mechanisms so they can be presented and discussed. In future installments, we will explore the potential mechanisms of these phenomena, and what these mechanisms may mean for the future.

This is the first of a three part series. I'm starting out with the topics listed above, and may move into diseases later on. My apologies if the first few installments are a bit below your knowledge base, but I want to make sure that everyone is on the same page. In the future, I may write a bit more on pathophysiology of the CNS (Alzheimer's, Parkinson's) and concepts of pain, reflexes, and somatic sensation.

The Neuron

The neuron is the functional unit of our nervous system. Neurons only make up a tiny fraction of the cells found in the central nervous system, but are the reason for the existence of all the cells around them. The astrocytes, ependymal cells, microglia, Schwann cells and oligodendrocytes (collectively known as the glia) exist only to support, protect, and serve the neurons. Neurons form the basis of thought, emotion, motion, sensation and every interaction that we have with or environment, and even our own bodies. They comprise our communication network, our sensory network, our processing center, and memory. But how do they work? You have probably heard that they are electrical in nature, but it's not the same thing as copper wire and solder. They are a lot more complicated, and require an introduction of a few concepts from cell biology. In the first installment of a three part series, I will talk about some of these basic concepts. From there, we can move on to a discussion of how signals get transmitted in the brain, and how certain drugs may affect that signaling.

The anatomy of a neuron

The classic neuron consists of three main parts : the soma, or cell body, the axon, and the dendrites. The soma is similar to the main cell body of any other cell in the body, except for the presence of synapses, which are discussed in the next edition. The cell body supports the rest of the cell, manufacturing proteins and peptides, shunting energy sources and waste products, and providing a genetic control center (the nucleus). Primary cell functions take place in the nucleus. The dendrites are are fingerlike projections that provide the input for the neuron. These receive input from other neurons, or in the case of sensory neurons, from the outside world. They can transmit this information in the form of electrical impulses to he cell body for transmission along the axon. A given neuron will have a very large number of dendrites, from dozens to thousands. The axon is a long, single, bifurcating projection from the neuron. This is the output. Only one axon leaves a neuron, but nearly all bifurcate into multiple treelike telodendria, which can also number in the thousands. Each telodendrite will terminate at an effector cell of another neuron. These connections are commonly in the form of a synapse, a point at which the two structures come exceptionally close, but do not actually touch. This synapse may be with an effector cell, such as a muscle or a gland, or with another neuron. In the brain, each neuron will receive input from, on average, 2000 synaptic endings. For an estimated 10^11neurons in the human brain, this means 200 trillion connections. By raw complexity, this outpaces the Pentium 4 processor by about six orders of magnitude.

The membrane potential

We are all familiar with diffusion, I hope. And we can all recall the high school biology class where we talked about semipermeable membranes, and the establishment of a concentration gradient. Well, every cell in out body has a concentration gradient set up of several different ions. The important ones for this discussion are sodium (Na), chloride (Cl), potassium (K), and calcium (Ca). Chloride is negatively charged. The rest are positive. Throughout our bodies, the levels of Na, Cl, and Ca are higher outside the cells than in. Potassium is higher inside. We are all aware of the tendency of these ions to move down their concentration gradient, or their chemical gradient, but many of us are probably not familiar with the idea of an electrical gradient. These ions are charged, and therefore set up an electrical potential across the membrane, which is determined by the small region of space directly on either side of the membrane. This thin region is known as the dipole layer. Ions outside this layer do not influence the membrane potential. By convention, the extracellular space is referenced as zero. Relative to that, the inside of a neuron is about -90mV when resting. This can change very easily, however, by altering the permeability of the membrane to certain ions. By regulating the flow of ions macros the membrane, you can transiently affect the voltage across the membrane. These changes are commonly referred to as hypopolarization (a decrease in the magnitude of the membrane potential), hyperpolarization (an increase in the magnitude of the membrane potential) and depolarization, which will be discussed in the next section. Remember: hypopolarization will actually be an increase in the potential. The resting potential is negative, so it must increase (become more positive) to approach zero.

So, how is this done? There are specific proteins in the membranes of cells called ion channels. These are controlled, or gated, in different ways. Some are opened by interaction with another molecule, either from outside or inside the cell. These are called ligand gated ion channels. Others are opened by mechanical forces. Many sensory neurons use these mechanically gated ion channels. Still others open in response to changes in the membrane potential, and are referred to as voltage gated ion channels. Recall the relative concentrations of ions. If a cell has a ligand gated sodium channel, and it is opened, positively charged sodium will flow into the cell, altering the electrochemical makeup of the dipole layer in that region, making it more positive. This will be a hypopolarization, or, in the case of a neuron, an excitatory potential. Alternatively, if a ligand gated chloride channel is opened, it will allow an influx of negatively charged chloride into the cell. This will result in a hyperpolarization of the membrane. To change things around a bit, imagine that a potassium channel opens. This would result in efflux of positively charged potassium from the cell, again hyper polarizing the cell.

Action Potentials

Remember the voltage gated ion channels? Most of these are sodium and potassium channels, and are found scattered along the axons of neurons. These typically open when the membrane potential reaches about -65mV, but this threshold can be modulated by the action of some neurotransmitters. When a local region of the membrane reaches or crosses this threshold, the voltage gated sodium channels in that region open rapidly. The resulting influx of sodium completely depolarizes the membrane, and the potential enters the positive domain. Some ions will diffuse along the membrane, altering the voltage in the neighboring regions. More voltage gated ion channels open in this region, depolarizing that region as well. This causes a cascade all the way down the axon.

Voltage gated sodium channels have two gates, one on the extracellular face and another on the intracellular face. In the resting state, the outer gate is closed and the inner gate is open. Upon crossing the threshold, the outer gate opens very rapidly, and the inner gate begins to close, but comparatively slowly. As a result, the gate remains open for only a short period of time, without the need for an additional outside force to act on the channel. The closing of the sodium channels prevents further influx of sodium, and the sodium that has flowed in begins to diffuse away from the membrane, deeper into the cell. Once the ions have left the dipole layer, they no longer influence the membrane potential and the potential can return to resting. Additionally, the same voltage that opens sodium channels stimulates a delayed opening of potassium channels. These do not fully open until the sodium channels have already begun to close, so they do not affect the membrane potential during this phase. Once they do open, they allow the efflux of potassium, which contributes to the reestablishment of the resting potential. Diffusion of sodium out of the dipole layer begins a slow repolarization, and the opening of the potassium channels initiates a rapid repolarization. The result is a sudden increase, then reestablishment of the membrane potential in one area, and this wave of depolarization propagates down the axon to the synapse.

One last feature of the sodium channels : the observant reader may have noticed that this should result in a continual series of action potentials, as that sodium from the next segment will diffuse in both directions. Sodium ions flowing backwards from the second segment to the first should raise the membrane potential there back to the threshold, reactivating the voltage gated sodium channels and repeating the depolarization. This, however, does not happen. Once a voltage gated sodium channel has been activated, it is no longer in its resting state. It now sits with its inner gate closed and its outer gate open, and it must be retooled. Anterograde propagation is prevented by the necessity of the channel to retool; it can only do so at the resting potential of -90mV. By the time the membrane returns to this potential, the action potential has propagated well beyond the range at which its sodium ions could affect the now responsive sodium channels.

So how is the membrane depolarized in the first place? This discussion begins with the assumption that a region of the membrane has crossed the -65mV threshold. How does this region of the membrane get to that potential? This is the function of the synapse : to control the membrane potential in a local region of the neuron via regulation of ion channels. This is the receptor potential, and we will discuss this in the next installment of the series.


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Display: Sort:
Membrane potentials, action potentials, and neurons | 59 comments (18 topical, 41 editorial, 1 hidden)
-1, Hyperpolarized voltage gated sodium channels (1.66 / 6) (#6)
by Pelorat on Fri Oct 22, 2004 at 08:46:02 AM EST

I hate those stupid fuckers.

Yeah, (3.00 / 13) (#33)
by davidduncanscott on Sat Oct 23, 2004 at 04:11:42 PM EST

they sold out after their second album.

[ Parent ]
Where is that K5ASCII Reenactment dude (2.00 / 3) (#28)
by JChen on Fri Oct 22, 2004 at 11:34:21 PM EST

when you need him?

PS- I got a C- in high school chemistry and cut out cardboard for general biology. I am also a social science major. Please make this make more sense to me!

Let us do as we say.

Glial Cells may do other things (3.00 / 2) (#32)
by whazat on Sat Oct 23, 2004 at 10:19:20 AM EST

Abstract of paper here

Good to see some science posted (none / 1) (#34)
by jd on Sat Oct 23, 2004 at 04:25:13 PM EST

It's rare enough, and the bulk of it is linking to other people's writings, rather than a solid piece like this. (Linking pieces have their place, but by nature don't actually add any new real information.)

Unfortunately, there are K5'ers who frown on anything calm, coherent and factual. The only other series I've seen make it through was one on physics and relativity. I'm pretty sure all of those made it to the front page, too. I genuinely hope this series does as well.

Amateurish (1.14 / 7) (#35)
by Requiem for a Dream on Sat Oct 23, 2004 at 06:34:15 PM EST

- no comment -

Hope you're not a crackpot. (none / 1) (#40)
by Sen on Sun Oct 24, 2004 at 01:51:21 PM EST

As one just starting out in this field, I see it's full of crackpots unlike perhaps any other (physics has its share). Why can't the loons go bug the kidney researchers? And why must philosophers feel they are qualified neuroscientists without knowing a bit of math or physics?

No Crackpot (3.00 / 2) (#44)
by Sgt York on Sun Oct 24, 2004 at 03:39:37 PM EST

I'm not going to present anything unconfirmed without labeling as such. I'm actually a physiology instructor at a MS nursing program, and the material here is a watered down version of some of what I teach.

I'm no philosopher, as evidenced by my lack of writing skills :). Actually, I'm a biochemist in training (about 1yr from my PhD, I hope)

There is a reason for everything. Sometimes, that reason just sucks.
[ Parent ]

Crackpots (none / 0) (#59)
by wurp on Wed Nov 17, 2004 at 05:30:44 PM EST

you're one of them
Buy my stuff
[ Parent ]
Ooh! Ooh! I have a question! (none / 0) (#45)
by OmniCognate on Sun Oct 24, 2004 at 06:00:38 PM EST

I'm just reading a book about this (Neuroscience by Bear, Connors and Paradiso). Perhaps they'll cover this one little detail later, but it's irritating me that I can't figure it out at this stage. I'm not at university, so it's not easy to find someone to ask. Lucky this article came along.

Why do Sodium-Potassium pumps pump 3 Sodium ions out of the cell for every 2 Potassium ions they pump in? It seems to me that you would need to pump equal numbers of the two ions.

Since the charge on a Sodium ion is the same as that on a Potassium ion, surely for every Sodium ion that comes in during the depolarisation phase of the action potential, one Potassium ion must leave during the repolarisation phase. Surely the same must be true for the slow leak of sodium in and potassium out when the membrane is at rest.

At least that's the way it seems to me. Perhaps that's not the case. Perhaps the two types of ions distribute themselves differently around the membrane, so that it takes a different number of each type of ion to build up the same potential difference. Different capacitances? Or am I gibbering?

You don't want the charges to be equal (none / 1) (#46)
by Sgt York on Sun Oct 24, 2004 at 07:19:39 PM EST

First, the transfer of ions during the AP is not necessarily equal. Pumps like the Na/K exchanger help maintain the balance. Second, during the resting phase, K leak is much greater (~100x) than Na leak. Third, the distribution of the ions is unequal. There is a ~1:14 ratio (in:out) Na and a 35:1 ratio for K (again, in:out).

Also, the membrane potential is determined by not only the concentrations of the ions on either side, but also by the permeability of the membrane to thise ions.

The Na/K pump helps maintain the net negative charge inside the cell. By having an outflow of 3+ and an inflow of 2+, you wind up with a net negative potential inside the cell. This adds to the membrane potential talked about in the article. There are also many processes that use the sodium gradient to do other kinds of work, like transport of substances across the membrane against their concentration gradient. Most of the K gradient is used to maintain the resting potential.

There is a reason for everything. Sometimes, that reason just sucks.
[ Parent ]

Nice one, thanks [n/t] (none / 0) (#48)
by OmniCognate on Mon Oct 25, 2004 at 04:01:53 AM EST

[ Parent ]
Size Selection (none / 0) (#58)
by Rhodes on Wed Oct 27, 2004 at 11:54:37 AM EST

I'm pretty sure that the pump is size selective- Sodium atoms / ions are much smaller than potasium atoms / ions.

[ Parent ]
pretty good job (none / 1) (#47)
by the_idoru on Sun Oct 24, 2004 at 10:25:28 PM EST

Well, I'm a doctoral student studying neurphysiology, and I think you did a pretty good job. But I know this stuff, so it makes sense to me. K5's format is really hurting you though, because it's supremely difficult to teach any of this without cartoons of cells, channels, or voltage traces. I mean, without a picture of an action potential, hypo-, hyper-, and depolarization are tough to figure. (I find that teaching the AP is hard enough even with them.)

Had I strolled by K5 while this was in editing. I'd have recommended explaining Na channels by describing them as a closed/open/inactive/closed cycle during the AP in addition to discussing the extra- and intracellular gates. Or maybe just not bother with the gates at all since there are no pictures. Also, you might want to explain "anterograde propagation" rather than just throwing it out there. You didn't mention how the electrochemical gradient is reestablished/maintained, but I think I saw that in a comment above.

Anyway, overall, pretty good. Looking forward to the others.

delicious (none / 0) (#53)
by orestes on Mon Oct 25, 2004 at 07:37:14 PM EST

an excellent piece, and some interesting points to add: the entire process of changing the membrane potential happens in about 2 milliseconds, give or take. considering the number of times this happens in a given moment, that's pretty amazing, at least in my eyes :)

also, the article notes that the membrane potential sits at about -90mV. looking around, different sources will say different numbers (my text happens to say -60mV, wiki says -80mV to -50mV, etc) - it's not an exact number (in case one looks elsewhere to find out more and has a stroke over the 30mV difference :) the important thing is that the stimulus causes a relatively drastic, fast change in membrane potential and a reversed sign - as in, from -70mV to about +40mV. probably best shown in pictures and graphs as said above, but this is still nice work.

[ You Sad Bastard ]
Myelin (none / 0) (#54)
by bob6 on Tue Oct 26, 2004 at 09:30:34 AM EST

The speed at which an action potential propagates along the axon is about 100ms-1. However this would not be enough in some cases (slow reflexes, for instance).

The mechanism described in the article is improved by myelin, which is a sheath of proteins and lipids layered around the axon. The sheath is intermittent along the axon leaving rings of uncovered membrane (which are called Ranier nodes, iirc). Since the myelin prevents ion exchanges through the membrane, the potential can occur only at the nodes. And since the axon cytoplasm is conductive, an action potential at one node causes a potential to the next node. Thus the potential doesn't propagate along the axon but jumps from a node to another.

Multiple sclerosis is caused by a defficiency in the myelin sheath.

Myelin (none / 0) (#55)
by Sgt York on Tue Oct 26, 2004 at 10:20:09 AM EST

Actually, the top conductance velocity is found in an A-alpha fiber, which is myelinated and normally tops out at around 120 m/s. Unmyelinated fibers conduct at about 1-2 m/s or less(off the top of my head).

And you were close...it's Nodes of Ranvier. The phenomenon you are talking about is called saltatory conduction.

There is a reason for everything. Sometimes, that reason just sucks.
[ Parent ]

Ah, yes. That's it. Univ memories... (none / 0) (#56)
by bob6 on Tue Oct 26, 2004 at 11:07:49 AM EST

I'm looking forward for the next chapters.

[ Parent ]
Membrane potentials, action potentials, and neurons | 59 comments (18 topical, 41 editorial, 1 hidden)
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