Human Physiology
Human Physiology

Human Physiology

Lead Author(s): John Redden, Joe Crivello

Student Price: Contact us to learn more

Focused on pure human physiology, this textbook uses interactivity to extend the subject beyond the page.

What is a Top Hat Textbook?

Top Hat has reimagined the textbook – one that is designed to improve student readership through interactivity, is updated by a community of collaborating professors with the newest information, and accessed online from anywhere, at anytime.


  • Top Hat Textbooks are built full of embedded videos, interactive timelines, charts, graphs, and video lessons from the authors themselves
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Key features in this textbook

Top Hat’s Human Physiology contains interactive diagrams, custom illustrations, pop-up definitions, and interactive 3D models to keep students actively engaged when learning the material.
Includes Focus on Disease, Thought Questions, and In the Clinic call-out sections that present key concepts in a relatable way for students to grasp!
Complete test bank of 400 questions for instructors to use.

Comparison of Human Physiology Textbooks

Consider adding Top Hat’s Human Physiology textbook to your upcoming course. We’ve put together a textbook comparison to make it easy for you in your upcoming evaluation.

Top Hat

John Redden & Joe Crivello, Human Physiology, Only One Edition needed

Pearson

Dee Unglaub Silverhorn, Human Physiology: An Integrated Approach (8th ed.)

Cengage

Lauralee Sherwood, Human Physiology: From Cells to Systems (9th ed.)

McGraw-Hill

Stuart Fox, Human Physiology (14th ed.)

Pricing

Average price of textbook across most common format

Up to 40-60% more affordable

Lifetime access on any device

$197.71

Hardcover print text only

$172.68

Hardcover print text only

$174.72

Hardcover print text only

Always up-to-date content, constantly revised by community of professors

Content meets standard for Introduction to Anatomy & Physiology course, and is updated with the latest content

In-Book Interactivity

Includes embedded multi-media files and integrated software to enhance visual presentation of concepts directly in textbook

Only available with supplementary resources at additional cost

Only available with supplementary resources at additional cost

Only available with supplementary resources at additional cost

Customizable

Ability to revise, adjust and adapt content to meet needs of course and instructor

All-in-one Platform

Access to additional questions, test banks, and slides available within one platform

Pricing

Average price of textbook across most common format

Top Hat

John Redden & Joe Crivello, Human Physiology, Only One Edition needed

Up to 40-60% more affordable

Lifetime access on any device

Pearson

Dee Unglaub Silverhorn, Human Physiology: An Integrated Approach (8th ed.)

$197.71

Hardcover print text only

Cengage

Lauralee Sherwood, Human Physiology: From Cells to Systems (9th ed.)

$172.68

Hardcover print text only

McGraw-Hill

Stuart Fox, Human Physiology (14th ed.)

$174.72

Hardcover print text only

Always up-to-date content, constantly revised by community of professors

Constantly revised and updated by a community of professors with the latest content

Top Hat

John Redden & Joe Crivello, Human Physiology, Only One Edition needed

Pearson

Dee Unglaub Silverhorn, Human Physiology: An Integrated Approach (8th ed.)

Cengage

Lauralee Sherwood, Human Physiology: From Cells to Systems (9th ed.)

McGraw-Hill

Stuart Fox, Human Physiology (14th ed.)

In-book Interactivity

Includes embedded multi-media files and integrated software to enhance visual presentation of concepts directly in textbook

Top Hat

John Redden & Joe Crivello, Human Physiology, Only One Edition needed

Pearson

Dee Unglaub Silverhorn, Human Physiology: An Integrated Approach (8th ed.)

Cengage

Lauralee Sherwood, Human Physiology: From Cells to Systems (9th ed.)

McGraw-Hill

Stuart Fox, Human Physiology (14th ed.)

Customizable

Ability to revise, adjust and adapt content to meet needs of course and instructor

Top Hat

John Redden & Joe Crivello, Human Physiology, Only One Edition needed

Pearson

Dee Unglaub Silverhorn, Human Physiology: An Integrated Approach (8th ed.)

Cengage

Lauralee Sherwood, Human Physiology: From Cells to Systems (9th ed.)

McGraw-Hill

Stuart Fox, Human Physiology (14th ed.)

All-in-one Platform

Access to additional questions, test banks, and slides available within one platform

Top Hat

John Redden & Joe Crivello, Human Physiology, Only One Edition needed

Pearson

Dee Unglaub Silverhorn, Human Physiology: An Integrated Approach (8th ed.)

Cengage

Lauralee Sherwood, Human Physiology: From Cells to Systems (9th ed.)

McGraw-Hill

Stuart Fox, Human Physiology (14th ed.)

About this textbook

Lead Authors

John Redden, Ph.DUniversity of Connecticut

John Redden has taught A&P for many years, from small to ultra-large classes. He currently serves as a National Academies Education Mentor in the Sciences Assistant Director of Faculty Development programs at the University of Connecticut’s Center for Excellence in Teaching and Learning.

Joseph F. Crivello, Ph.DUniversity of Connecticut

Joseph F. Crivello has taught A&P for the past 34 years. He is currently a Teaching Fellow of the HHMI/Hemsley Summer Teaching Institute and is the Premedical Advisor to the University.

Contributing Authors

Melissa MarcucciUniversity of St. Joseph

Melissa FoxWingate University

Angela HessBloomsburg University of Pennsylvania

Andrew LokutaUniversity of Wisconsin

Kristen KimballUniversity of Connecticut

Michele MooreButler University

Matthew OrangeCentral Connecticut State University

Chad WayneUniversity of Houston

Gerald BrasingtonUniversity of Southern Carolina

Kira WersteinIowa State University

Bruce PichlerUniversity of North Georgia

Ron GerritsMilwaukee School of Engineering

Chris TrimbyWisconsin Institute for Science Education & Community Engagement

Adam SullivanBrown University

Explore this textbook

Read the fully unlocked textbook below, and if you’re interested in learning more, get in touch to see how you can use this textbook in your course today.

Chapter 5: Excitable Cells

Figure 5.1. In the famous horror movie Frankenstein, electricity was used to reanimate the dead.​ [1]


5.1 Objectives

After completing this chapter, you should be able to:


5.2 Introduction

​In the early 19th century, the scientist Luigi Galvani accidentally touched his metal scalpel to a muscle in a dissected frog leg and observed a subtle twitch. That small observation gave birth to an entire field of study dedicated to understanding how excitable cells like muscle and neurons generate, propagate, and send electrical signals. Throughout the 19th century, curious scientists attempted to build on Galvani’s work by electrocuting limbs, heads, and even entire cadavers to better understand the link between electricity and the physiology of muscle and nervous tissues. If this sounds like the plot of a horror story, it is. Many people credit these early “reanimation” experiments with being the inspiration for Mary Shelley’s famous novel Frankenstein.

​Originally called Galvanism, the study of excitability is referred to as electrophysiology by modern scientists. Nearly 200 years since the field began, we now understand that electricity is a major method of signaling and cell to cell communication used by the nervous system and muscle tissue. While this electricity is similar to the electricity carried within a wire conceptually, there are some differences that will be explored later. In this chapter, we will explore how electrical signals are generated in a biological system and then talk specifically about excitability in neurons (muscle excitability depends on these same principles, but is covered in its own chapter later in the text). Excitability is often a challenging subject for students because it is based on things that are impossible to see and difficult to imagine. Don’t be discouraged – it has been a challenging area of study for scientists too! However, understanding many of the systems we will talk about later in the textbook will require applying your knowledge of excitability. As we move through this chapter we will briefly review some key points about membrane transport that you learned about in the cell biology chapter, but if you don’t have a good grasp on the concepts of diffusion and carrier mediated transport, then it’s recommended you revisit that chapter before working through this one.

Question 5.01

What is one thing that you would like to learn about how excitable cells function?


5.3​ Creating Membrane Potential in a Biological System

​At the most basic level, excitability refers to the ability of a cell to send and receive electrical signals across the plasma membrane. Recall that as a lipid bilayer, the plasma membrane is semi-permeable, which creates compartmentalization of many substances including water, glucose, enzymes, and most importantly, ions. This means that the concentration of an ion like potassium is going to be different in the cytosol (inside the cell) than in the interstitial fluid (outside the cell) – in other words, there is a concentration gradient for potassium. The table below summarizes the differences in the concentration of the key ions that we will be dealing with in this chapter between the intracellular and extracellular environment of a typical neuron.

​Table 5.1. Typical ion concentrations inside and outside of a neuron.​


TQ 5.01

How are concentration gradients created within a cell?

Hover here to see the answer to Thought Question 5.01.


Question 5.02

Using table 8.1 above, sort the following ions from the highest concentration inside a cell to the lowest:

A

Chloride

B

Sodium

C

Potassium

D

Calcium

If you aren’t a fan of numbers, that’s ok! In most cases, representing concentrations visually works too, as shown below:

ANP08_ConcentrationGradients_hires.jpg
Figure 5.2. A visual representation of concentration gradients for common ions. Arrows indicate the direction of passive movement.

​Concentration gradient describes the difference in concentration of a substance between two compartments. In other words:

                                                               Gradient  =  [Ion]outside    [Ion]inside​\mathrm{Gradient}\;=\;\lbrack\mathrm{Ion}\rbrack_\mathrm{outside}\;–\;\lbrack\mathrm{Ion}\rbrack_\mathrm{inside} 

​Because sodium (Na+) concentration is 150mM outside the cell and 15mM inside the cell, the concentration gradient for Na+ is 135mM.

                                                 Na+  Gradient=(150mM50mM)=  100mM\begin{array}{rcl}\mathrm{Na}^+\;\mathrm{Gradient}&=&(150\mathrm{mM}-50\mathrm{mM})\\&=&\;100\mathrm{mM}\end{array} 

 Conceptualizing a gradient can be difficult, so it’s good to get in the habit of picking your favorite method (number or pictures) and apply it whenever you need to calculate one. For example, what happens to the gradient if [Na+]inside is changed to 50mM?

                                                 Na+  Gradient=(150mM50mM)=  100mM\begin{array}{rcl}\mathrm{Na}^+\;\mathrm{Gradient}&=&(150\mathrm{mM}-50\mathrm{mM})\\&=&\;100\mathrm{mM}\end{array} 

In this situation, the concentration gradient has decreased (or become smaller). If, instead, the concentration of Na+ inside was changed to 5mM, the concentration gradient would increase (or become larger).

Question 5.03

Using the information in this table, calculate the concentration gradient for calcium (in mM).

question description


Question 5.04

If the concentration of extracellular calcium is changed to 1mM, what happens to the concentration gradient?

A

It increases

B

It decreases

C

It stays the same

​Understanding the concept of concentration gradient is important for learning about membrane potential, because the concentration gradient will allow you to easily predict the direction in which ions will move across the membrane if it is permeable to that ion. In the cell biology chapter, you learned that a major mechanism for ion transport across the plasma membrane is through ion channels. The stimulus required to open or activate an ion channel is known as its gate mechanism – we will talk about many ion channels throughout the text, and gating mechanisms will almost always be a major focus. In this chapter, we will be talking about two major classes of ion channels.

Figure 5.3. Ion channels discussed in this chapter are gated by membrane potential (voltage gated, left) or neurotransmitters (ligand gated, right)​.

Ligand-gated ion channels are channels that are gated by a chemical messenger (a ligand) on the inside or outside of the cell. These channels contain a receptor for a hormone or neurotransmitter that, when bound, will cause the channel to open and create a pore through the membrane. Some channels may close in response to ligand binding as well.

Voltage-gated ion channels are channels that are gated by a change in the charge of their surrounding environment inside the cell. For example, the internal membrane region surrounding one of these channels becoming more positive or negative will be sensed by charged amino acid residues that make up the protein. In response, the protein will change conformation, causing these channels to open and create a pore through the membrane.

​A key point to keep in mind is that ion channels only allow passive transport. As a consequence, despite some very complicated gating mechanisms, open channels only allow ions to move down their concentration gradients (e.g., from regions of relatively higher concentration to regions of relatively lower concentration). The greater the concentration gradient is for an ion, the greater the diffusive flux will be for that ion. Remember that “flux” refers to the flow of an ion between the two compartments, and in this example, there will be more. For a review of simple diffusion and membrane transport mechanisms, you may want to refer back to the chapter on Cell Structure and Function earlier in the text.

Question 5.05

Assuming Na+^++ is permeable, what would happen if the outside concentration of Na+^+ in the table above changes from 150mM to 200mM?

A

More Na+^+ ions enter the cell.

B

Fewer Na+^+ ions enter the cell.

C

There is no change.

Also, keep in mind that most ion channels are selective for specific types of ions. A voltage-gated Na+ channel, when activated, will allow Na+ to cross the plasma membrane but not potassium, chloride, or calcium. This specificity is due to differences in the charges of the amino acids that make up the ion channel, how those amino acids interact with ions, and the physical size of the ions attempting to pass through the pore (e.g., a Na+ ion is smaller than a potassium ion). A ligand-gated potassium channel, when its receptor is engaged, will only allow potassium ions to move across the membrane, but not Na+, chloride, or calcium. A typical neuron contains more than 300 different ion channels that vary in their gating mechanisms and selectivity. Fortunately, using the concentration gradients in the table above, we can make some important generalizations:

  • Potassium leaves the cell passively via channels (because it has a higher concentration inside and lower concentration outside).
  • Naenters the cell passively via channels (because it has a higher concentration outside and lower concentration inside).
  • Chloride enters the cell passively via channels (because it has a higher concentration outside and lower concentration inside).
  • Calcium enters the cell passively via channels (because it has a higher concentration outside and a lower concentration inside).

​Because of homeostasis, relative concentrations are constant in a healthy person (e.g., potassium is always higher inside the cell than outside). However, this is a common point of misconception for students learning about membrane potential for the first time. What happens if you put a drop of blue food coloring in a glass of water? What if you put it in the ocean instead? Adding drops of blue food coloring to the ocean will not change its color, though it will turn a glass of water blue. This difference demonstrates the relationship between volume and concentration – your cells are like the ocean. Despite the movement of thousands of ions per second through an open ion channel, the relative concentration gradients never change because of the large cytoplasmic volume. The concentration of sodium is always going to be approximately 10 times greater outside the cell than inside. The millions of molecules that move represent only a tiny fraction of the total number of ions present in the compartment they are moving from.

​In contrast to the above, moving ions against their concentration gradients (from regions of relatively lower concentration to regions of relatively higher concentration) is an active transport process and cannot occur through channels. Instead, this occurs through transporters and pumps. Excitable cells depend on both channel mediated and carrier mediated transport to function properly.

Question 5.06

What type of transport is required to move sodium ions out of the cell?

​The final thing that we have to consider is that ions are charged particles. Anions (like chloride) have a negative charge, and cations (like potassium, calcium, and sodium) have a positive charge. This is actually the most important point to be made when talking about excitability for the following reasons:

  • If ions are unevenly distributed across the membrane, then there is uneven distribution of charge across the plasma membrane.
  • If ions are permeable and being transported across the membrane, then the charge distribution across the plasma membrane is also changing.

​Because ions are charged particles, their movement is influenced by more than just concentration gradient, it is influenced by electrostatic forces. Do you remember playing with magnets as a child? If you do, then you are already familiar with the concept of electrostatic forces – like charges repel, and opposite charges attract. Suppose you have two magnets, each with a positive and negative end. If you place the two positive ends together, you can feel the electrostatic force causing the ends of the magnets to repel each other, pushing your hands away. However, placing the positive end of one magnet next to the negative end of your second magnet will result in attractive electrostatic forces sticking the two magnets together. The ions within your cells are subjected to these exact same forces.

Figure 5.4. Ions are charged particles subject to electrostatic forces. Opposite charges attract, whereas like charges repel.​

​Let’s extend this childhood memory a bit further (don’t get too nostalgic, we will get back to college stuff momentarily). Electrostatic forces can be powerful, but they do not work from great distances. In other words, the two ends of your magnet had to be brought pretty close together in order for the electrostatic forces to engage. Once they were close together, however, they were nearly unstoppable.

  • ​Electrostatic forces are highly localized. They work best when they are close together, and poorly when far away. This means that when charges (ions) move, the changes can only be felt in the immediate membrane area they moved into (or out of).
  • ​Keeping charges separated requires energy input. This is why active transporters are so important – they maintain the gradients!

​In excitable cells, the selectively permeable plasma membrane serves as an insulator that keeps charges separate from each other so that the electrical potential outside the cell is different from the electrical potential inside the cell. This difference in charge between the two environments creates a form of potential energy known as membrane potential. You might not think of the plasma membrane as a “battery”, but from an electrical standpoint, it is!



Figure 5.5. Comparison of common household batteries.​ [2]

​The batteries shown above also separate charges and create an electrochemical gradient between their two terminals. When you connect batteries to an electronic device, your device creates a path for current to move between the positive and negative terminals and provide power to your device. Allowing charged particles (ions) to move across the membrane through ion channels, also changes the electrochemical gradient, and allows cells to use the stored energy (membrane potential) for many critical cellular processes. Every battery has a specific voltage, as do all excitable cells inside your body. Fortunately, this is something that can be easily measured experimentally by placing a recording electrode inside the cell, and a reference electrode in the extracellular fluid. These electrodes attach to a voltmeter, which can calculate the difference in potential sensed by the two electrodes. In a typical neuron, this difference is calculated to be approximately –70 mV. In a biological system, it is a measure of the cells’ ability to do work (by allowing ions to pass through the plasma membrane).

Figure 5.6. Membrane potential can be measured experimentally using two electrodes connected to a voltmeter. By convention, the recording electrode is placed within the cell, and a reference electrode is placed in the extracellular fluid. The voltmeter compares the difference in charge between these two regions.​


5.4​ The Nernst Equation Calculates Equilibrium Potential

To summarize the major points that we have made up to this point in the chapter:

  • Ions have a concentration gradient across the plasma membrane. 
  • Ions will move down their concentration gradient through ion channels.
  • Ions, because they are charged particles, are subjected to electrostatic forces that influence their movements.

Which of these two forces, concentration gradient or electrostatic potential, is most important for determining ion movements? Do they work together, or against each other? As an example, recall that the relative concentration of sodium is much greater outside the cell. If a sodium channel opened in the plasma membrane, sodium would enter the cell because of its concentration gradient. However, sodium also has a positive charge that would be electrostatically attracted to the slightly negative charge inside the cell. In this situation, the two forces are working together to bring sodium in! Eventually, however, its entry would be slowed and stopped by the accumulation of positive charges inside the membrane because of like charge repulsion. This is an example of an electrochemical equilibrium – the chemical force of sodium moving down its concentration gradient is balanced by electrostatic repulsion of the positively charged sodium ions and the (now) positive intracellular environment. At this equilibrium point, the net flux of sodium across the membrane is zero even if the ion channels remain open. This is similar to what would happen if you had a spring attached to a weight, as in the image below.

Figure 5.7. A weighted spring provides a conceptual representation of the forces that create membrane potential.​

​The spring is initially pulled downward by the weight, then will recoil upward, be pulled back down again, and back up …, etc., until it eventually balances out at some point. We could say that at this point, the spring is at equilibrium between the effects of gravity (downward) and the recoil of the spring (upward). When talking about ions, the electrochemical equilibrium point is known as the Equilibrium or Nernst Potential, and is calculated using the Nernst Equation:

                                                                    Eion=61.5mVz  log10[ion]out[ion]in\mathrm{E_{ion} = \dfrac{61.5 mV}{z} \ \cdot \ \dfrac{log_{10}[ion]_{out}}{[ion]_{in}}}

Equations can often be intimidating at face value, but hopefully after this chapter, you will come to see them as a secret weapon for getting the right answer every single time because they can make abstract concepts seem a bit more concrete. The Nernst Equation looks complicated (Walther Nernst won a Nobel prize in Chemistry for his work on chemical equilibrium) – what is shown above is actually a simplified version! But taking a closer look at the terms within it individually makes it a lot less scary.

                                                                 Eion=61.5mVz  log10[ion]out[ion]in​\mathrm{E_{ion} = \dfrac{61.5 mV}{z} \ \cdot \ \dfrac{log_{10}[ion]_{out}}{[ion]_{in}}} 

  • The first term in the equation, Eion, is the equilibrium potential for an ion. This tells us that the Nernst equation can only be used to calculate the electrochemical equilibrium for one type of ion. For example, the equilibrium for potassium would be represented as EK.
  • The second component of the equation, 61.5 mV, is a constant that assumes the cell is at 37 degrees Celsius.
  • The third term in the equation, log[ion]in/[ion]out, refers to the concentrations of the ion inside the cell ([ion]in) and outside the cell ([ion]out). Note: the log of 1 is zero. This means that if there is no concentration gradient, equilibrium potential is zero.
  • Finally,  the z corresponds to the charge of the ion. For example, Potassium is +1, Chloride is –1, …, etc.

​Setting aside the constants (because they are constant), the Nernst equation essentially says that the electrochemical equilibrium for an ion depends upon the concentration gradient for that ion and the charge of that ion. This should make sense if you have already read the earlier sections of this chapter. Because every ion has a different concentration gradient and a different charge, it’s worth repeating that equilibrium potential is unique for every ion. The other big assumption of the Nernst equation is that the cell is permeable to the ion. For these reasons, it might be helpful to think of an ion’s equilibrium potential as a “what if” scenario. What would the potential across the membrane be if the cell were permeable to potassium and nothing else, and we allowed potassium ions to reach their electrochemical equilibrium? Equilibrium potentials for the major ions are calculated in the table below:

Table 5.2. Equilibrium potentials can be calculated from ion concentrations inside and outside the cell​.​​

In other words, if a cell is made permeable to potassium, potassium ions will leave the cell down their concentration gradient until the potential of the cell is -89.0 mV. If the cell were made permeable to sodium instead, sodium would enter the cell until the potential of the cell was +61.5 mV. of the ion.

If you need to know an equilibrium potential, you can always calculate it using the Nernst equation. However, equilibrium potentials generally do not change inside the body because ion concentrations are regulated homeostatically (and because the charge of an ion never changes), so memorizing their relationships relative to each other will allow you to make some quick calculations that will be helpful later. For example, potassium has the most negative equilibrium potential, and sodium has the most positive equilibrium potential.

But what would happen if the potassium concentration outside the cell was changed to 20mM? Here are some things to consider to tackle this problem conceptually:

  • ​In the new condition, is there a concentration gradient? 

     Yes

  • Is the concentration gradient larger or smaller? 

     Smaller

  • In which direction does the ion move

    Out

  • Is there more ion movement, or less ion movement? (Hint: increasing the concentration gradient increases diffusion) 

     Less movement

  • What is the charge of the ion? 

     Positive

  • What happens to equilibrium potential because of steps 4 and 5? 

     Less K flows out, so the equilibrium potential becomes more positive.

To double check, we can always plug the new values into the Nernst equation. If extracellular potassium was changed to 20mM, then the new equilibrium potential would become -51.97 mV, which is more positive than the original equilibrium potential of -89.0 mV. Use the Nernst equation calculator below to see how the equilibrium potential changes as the concentration of ions across the membrane changes:​

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Question 5.07

If [K]out_{out} is changed to 150mM, what happens to EK_K?

A

It becomes more positive.

B

It becomes more negative.

C

It stays the same.

D

It becomes zero.


Question 5.08

If [K]in_{in} is changed to 5mM, what happens to EK_K?

A

It becomes more positive.

B

It becomes more negative.

C

It stays the same.

D

It becomes zero.


Question 5.09

If [K]in_{in} is changed to 150mM, what happens to EK_K?

A

It becomes more positive.

B

It becomes more negative.

C

It stays the same.

D

It becomes zero.


While equilibrium potentials are very important, equilibrium potential is not the same thing as membrane potential (Vm). This is because the Nernst equation assumes that the cell is only permeable to a single type of ion, but living cells are always permeable to more than one type of ion at a time. The relative permeability, P, of the major ions in a typical neuron are as follows:

Table 5.3. Representative concentrations of important ions (neuron) in the intracellular and extracellular fluid, equilibrium potentials, and relative permeability.​

​As you can see, while cells are permeable to more than one ion, they are not equally permeable. Therefore, if all ions that are permeable are trying to reach their electrochemical equilibrium at the same time, we can think of membrane potential as a weighted average of the equilibrium potentials of all permeable ions. Membrane potential can be calculated by what is known as the parallel conductance equation:

                                                                   Vm=gKEK+gNaENa+gClEClgK+gNa+gClV_m = \dfrac {g_KE_K + g_{Na}E_{Na}+g_{Cl}E_{Cl}}{g_K+g_{Na}+g_{Cl}}

 Vm = Membrane potential
Eion = Equilibrium potential for a particular ion
g = Conductance

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Conductance (g) is the ability of an ion to carry a current across the membrane. Although not exactly the same as permeability, which is the ability of an ion to move across the membrane, the two terms are closely related. If permeability increases to an ion, then the conductance of that ion should increase (and vice versa). It is possible to calculate membrane potential using permeability and concentration gradients in an alternative equation, called the Goldman-Hodgkin-Katz Equation:

                                           Vm=RTFln(PNa[Na]out+PK[K]out+PCl[Cl]inPNa[Na]in+PK[K]in+PCl[Cl]out) V_m=\dfrac{RT}{F}\mathrm{ln}(\dfrac{P_{Na}[Na]_{out}+P_K[K]_{out}+P_{Cl}[Cl]_{in}}{P_{Na}[Na]_{in}+P_K[K]_{in}+P_{Cl}[Cl]_{out}})

As we have already mentioned, concentration gradients do not significantly change in a healthy individual because they are maintained through homeostatic mechanisms. This means that in an excitable cell, the primary mechanism to change membrane potential is to change conductance (permeability). In other words, cells open and close ion channels for the various ions! Essentially, you can think of membrane potential as a “tug of war” between the equilibrium potentials of all of the ions that are permeable, and the strength of each ion’s “pull” depends upon its permeability. Assuming that the concentration gradients are not changing, this means that if we know the equilibrium potentials for sodium and potassium, we also know the range of possible membrane potentials that the cell may experience. For example, if EK is –89 mV, then the membrane potential cannot become more negative than –89 mV. Similarly, if ENa is +61.5 mV, then the membrane potential cannot become more positive than +61.5 mV. Any change in conductance will only cause the membrane potential to fluctuate to some point between Ek and ENa. In other words, ENa represents the “ceiling” and EK represents the “floor” for the membrane potential in a typical cell.​

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5.5​ Resting Membrane Potential

Figure 5.8. A membrane is in a steady state when ions are moving across the membrane at equal and opposite rates (zero net flux). This is similar to the situation represented by the above image. A constant water level inside the bucket appears despite movement in and out.

​Most excitable cells reach a steady state known as resting membrane potential that can be calculated using the parallel conductance equation. This is the point where the movement of all ions is equal and opposite across the membrane (net flux is zero) – however, it is not a point where ions have stopped moving. Imagine steady state as a bucket that is being filled with water but has a hole in the bottom – it is filling and draining at equal rates. If you take pictures of the bucket, the water level will appear to be the same in each photo, but that doesn’t mean that water isn’t entering and leaving the bucket.

Table 5.4. Representative concentrations of important ions (neuron) in the intracellular and extracellular fluid, equilibrium potentials, and relative permeability. ​

We can calculate resting membrane potential by inserting values from the table above into the following equation:

                                         Vm=RTFln(PNa[Na]out+PK[K]out+PCl[Cl]outPNa[Na]in+PK[K]in+PCl[Cl]in) V_m=\dfrac{RT}{F}\mathrm{ln}(\dfrac{P_{Na}[Na]_{out}+P_K[K]_{out}+P_{Cl}[Cl]_{out}}{P_{Na}[Na]_{in}+P_K[K]_{in}+P_{Cl}[Cl]_{in}}) 

Resting membrane potential, as we have already mentioned above, is negative. If we put resting membrane potential on a number line alongside the equilibrium potentials we can see that it is very close to, but not equal to, potassium’s equilibrium potential.

Figure 5.9. The membrane resting potential is mostly affected by membrane permeability to potassium.

​Again, this is because neurons have the highest relative permeability to potassium at resting membrane potential. In other words, potassium is winning the “tug of war” because of its high permeability. The high permeability to potassium at rest is due to leaky potassium channels, which are always open at physiological membrane potentials. In other words, there is a constant efflux of potassium from the cell. In subsequent sections of this chapter, we will be discussing changes from resting membrane potential, so it’s really important that you feel comfortable with the concepts of membrane potential and resting membrane potential before moving forward. In order to predict how a cell will change its resting membrane potential, let’s lay down a few rules that apply the terminology we have introduced:

  • If the permeability to an ion increases, then resting membrane potential will move toward that ion’s equilibrium potential (e.g., if sodium channels open, then membrane potential will move from rest to something more positive, since sodium’s equilibrium potential is very positive).
  • If the permeability to an ion decreases, then resting membrane potential will move away from that ion’s equilibrium potential (e.g., if a potassium channel closes, then membrane potential will move from rest to something more positive, since potassium’s equilibrium potential is very negative).
Question 5.10

If PNa_{Na} is changed to 0.4, what happens to Vm_m?

A

It becomes more positive.

B

It becomes more negative.

C

It stays the same.

D

It becomes zero.


Question 5.11

If PCl_{Cl} is changed to 0.8, what happens to Vm_m?

A

It becomes more positive.

B

It becomes more negative.

C

It stays the same.

D

It becomes zero.


Question 5.12

If PK_K is changed to 0.2, what happens to Vm_m?

A

It becomes more positive.

B

It becomes more negative.

C

It stays the same.

D

It becomes zero.


Although concentration gradients do not typically change, changing the concentration gradient changes equilibrium potential, and membrane potential is also affected. This often happens during disease.

Question 5.13

If [Na]out_{out} is changed to 160mM, what happens to Vm_m?

A

It becomes more positive.

B

It becomes more negative.

C

It stays the same.

D

It becomes zero.


Question 5.14

If [K]in_{in} is changed to 1mM, what happens to Vm_m?

A

It becomes more positive.

B

It becomes more negative.

C

It stays the same.

D

It becomes zero.


TQ 5.02

Changes in membrane potential serve as signals to cells within the body – and can often be a drug target in the treatment of many diseases. However, membrane potential is also the target of many toxins that disrupt various cellular processes. Lethal injections, for example, commonly follow a three-step procedure: the first drug is a sedative, the second drug causes muscle paralysis, and the third drug, the one that actually kills, is potassium chloride. What happens to membrane potential when potassium is injected at this very high concentration?

Hover here to see the answer to Thought Question 5.02.


We can summarize everything we have learned so far as:

  • Membrane potential is created by the uneven distribution of ions across the membrane.
  • Membrane potential changes when ion concentration gradients change, or when changes in permeability (e.g., opening and closing ion channels) change the movement of flux of ions across the membrane.

Now let’s discuss how neurons use changes in membrane potential for cell to cell communication.

5.6 Neuronal Physiology

​Neurons are the major cell type that the body uses for communication. As excitable cells, neurons can detect a stimulus and transduce it into an electrical signal.


Question 5.15

Place the following structures in the order they would be encountered in a post-synaptic cell:

A

Axon

B

Axon hillock

C

Ligand-gated channels

D

Soma

E

Axon terminal

F

Dendrites

G

Voltage-gated channels


A neuron has a cell body that is similar to other cells, but it has extended membrane processes that make it unique from other cell types. These processes are dendrites and axons, and can project as a single process or as a highly branched structure. Each neuron contains a large cell body with a single nucleus. Within the neuronal cell body, filaments separate areas of rough endoplasmic reticulum known as Nissl bodies. Nissl bodies are the sites of extensive protein synthesis. The majority of protein synthesis occurs in the cell body, less occurs in dendrites, and almost none occurs in the axon. Proteins and other materials are transported from the cell body to the ends of both dendrites and axons (anterograde transport, from the cell outward), as well as back to the cell body (retrograde transport, from the periphery back to the cell).


TQ 5.03

Why is a transport system necessary within the neuron?

Hover here to see the answer to Thought Question 5.03.


Question 5.16

Pre-synaptic inhibition is a process where a neurotransmitter binds to a neuron and prevents that neuron from releasing neurotransmitter into the synapse. On which region of the neuron would you expect to find these receptors?


The neuronal cell body also contains an extensive Golgi apparatus surrounding the nucleus, with many mitochondria and other cell organelles. Large numbers of intermediate filaments and microtubules form bundles that project through the cytoplasm in all directions and form the basis of the cytoskeleton and transport systems.

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​Dendrites are thin membrane projections that have a greater diameter than axons. Dendrites are filled with small amounts of cytoplasm and contain numerous ribosomes that synthesize the important transport proteins and neurotransmitters required for a neuron to function. Many are decorated with thousands of even tinier projections called dendritic spines. The dendritic spines contain a wide variety of ligand-gated and voltage-gated ion channels. Functionally, dendrites integrate information received from other neurons or sensory receptors and transfer that information in the form of electrical currents throughout the cell membrane.

In most neurons, a single axon arises from a cone-shaped area of the cell body called the axon hillock. The beginning of the axon is termed the initial segment, also known as the trigger zone because of the high density of voltage-gated Na+ channels. An axon is often a single membrane projection, but can also be branched. Axons vary in length from 100 mm to more than 1 meter (e.g., from the base of the spine to the bottom of your foot). At the end of the axonal membrane, the membrane branches and forms enlarged ends that lie close to other cells and form synapses. Information is transferred from the axonal membrane to other cells by neurotransmitters or electrical currents. In some cells, it is impossible to visually differentiate between axons and dendrites; the function of the cell process must be determined to identify axons or dendrites in these cells.

In many cases, the axonal membrane is myelinated, covered by additional layers of cell membrane produced by glial cells(the significance of myelin is discussed later in this chapter). There is a great deal of retrograde and anterograde transport to and from the cell body. Proteins, organelles, vesicles, and other components are transported through the axon. Damaged organelles, recycled plasma membrane, and substances taken up by endocytosis in the dendrite are transported toward the cell body. In fact, many infectious agents, like rabies or herpes viruses, are transferred to the central nervous system from peripheral nerves by retrograde transport.

Forming precise connections between neurons and specific target cells is a critical function of the nervous system. During development these connections, known as synapses, form, stabilize, and may even be eliminated depending on the amount of communication between neurons and a particular target cell. Neurons regulate many tissues, including muscle cells, other neurons, and glands. The synapse (discovered by the Spanish anatomist and scientist Ramon y Cajal) has three parts. The end of the axonal membrane swells to a bud-like structure in close contact with another cell. This terminal is the pre-synaptic (before the synapse) membrane and is typically the cell that is “sending” the message. The membrane of the target cell is the post-synaptic (after the synapse) membrane, which “receives” the message. Between these two membranes lies the synaptic cleft, which is a gap between the two cells that is filled by interstitial fluid. The successful relay of messages between pre- and post-synaptic cells through the synapse creates a synaptic potential.

5.7 Synaptic Physiology

​Depending on the region of the cell, neurons produce two major types of changes in membrane potential. Graded potentials are most often produced in the dendrites and soma, and action potentials are classically thought to be produced in the axon. Although it is now known that these regional distinctions are an oversimplification (e.g., a neuron can produce dendritic action potentials), we are going to continue to use them as a  framework to understand neural communication. In other words, it’s better to learn the rules before worrying about the exceptions!

We have already established that neurons have a resting membrane potential, which is the membrane potential at which the cell will remain in the absence of a change in ion permeability. For this reason, membrane potential is usually represented using a line graph, with membrane potential (measured in mV) on the y-axis and time (measured in milliseconds) on the x axis, as below.

​Figure 5.10. Transient changes in membrane potential are often represented similar to the graph above as a change in voltage (y-axis) over time (x-axis).​

Most synapses are axodendritic synapses, which means that the dendrites (or more specifically, the dendritic spines) on a post synaptic cell are commonly the site of signal input. In other words, they receive messages. This is because pre-synaptic cells release neurotransmitter onto receptors located on the dendrites of these post-synaptic cells. Receiving chemical messages requires neurons to express many ligand-gated ion channels, which have complementary receptors for the neurotransmitter, on the dendrites and soma. Since the binding of neurotransmitter controls the gating of the channels, this creates a change in ion permeability and a change from resting membrane potential.  Depending on the identity of the channel, and whether it opens or closes upon neurotransmitter binding, there are two potential changes that can occur:

  • Membrane potential can move from rest to a more positive value. This is known as depolarization.
  • For example, opening a ligand-gated sodium channel increases the permeability to sodium and allows positively charged sodium ions to enter the cell (recall [Na]out is higher). According to the parallel conductance and G–H–K equations we introduced earlier in the chapter, this causes membrane potential to move closer to ENa (+61.5 mV).
  • Membrane potential can move from rest to a more negative value. This is known as hyperpolarization.
Figure 5.11. Specific terms (depolarization, repolarization, hyperpolarization) are used to describe specific changes in membrane potential.​​​
  • Opening a ligand-gated potassium channel increases the permeability to potassium and allows positively charged potassium ions to leave the cell (recall [K]in is higher). According to the parallel conductance or G–H–K equation, this causes membrane potential to move closer to EK (-89.5 mV).
Question 5.17

Increasing sodium permeability from rest would lead to what type of change in membrane potential?


Question 5.18

Increasing potassium permeability from rest would lead to what type of change in membrane potential?


Question 5.19

Decreasing sodium permeability from rest would lead to what type of change in membrane potential?


Since these changes in Vm are occurring on the post-synaptic cell as a result of communication through the synapse, graded potentials in the dendrites are often referred to as synaptic potentials.

  • A depolarizing synaptic potential is known as an Excitatory Post-Synaptic Potential (EPSP). This can be represented graphically as:
Figure 5.12. An excitatory post synaptic potential (EPSP)​.​
  • A repolarizing synaptic potential is known as an Inhibitory Post-Synaptic Potential (IPSP). This can be represented graphically as:
Figure 5.13. An inhibitory post synaptic potential (IPSP).​

This video reviews how synaptic potentials are generated and measured as changes from resting membrane potential.

Because they are usually the result of ligand-gated channel opening (and therefore passive ion transport), both EPSPs and IPSPs are limited by diffusion. Remember from earlier in the text that membrane potential is restricted to the local membrane region that the ions are moving out of or into.

Figure 5.14. Synaptic potentials are graded potentials that begin at an open ligand gated ion channel and spread through diffusion.​

​Going back to the analogy we used earlier in the chapter, if you put a drop of blue food coloring in a swimming pool you wouldn’t turn the water more blue. In fact, you would only see that blue drop for a split second at the exact site that it hit the water. This is what happens with EPSPs and IPSPs. If we were to measure membrane potential at the site where neurotransmitter was being released, we would see a bigger change in Vm than if we measured a region further away. This is because graded potentials are decremental. In other words, the further away from the site of neurotransmitter release (and channel activation) we travel on the plasma membrane, the smaller the change in membrane potential.

​Figure 5.15. A graded potential, recording from different regions of the neuron simultaneously. The further from the point of origin, the weaker the change in membrane potential will be.​

Would it make any difference in the above scenario if you were to add fifty thousand drops of blue food coloring? What if you and 500 friends all added a drop at the same time? This later scenario more accurately describes what is happening, since pre-synaptic cells release large quantities of neurotransmitter. As a result, a neuron doesn’t produce just a single EPSP or IPSP at a time, it produces many! One of the important features of synaptic potentials is that they can undergo temporal summation and spatial summation, which allows changes in membrane potential to be added together or summed. In other words, bringing in sodium ions produces an EPSP until those sodium ions diffuse out of that membrane area. If more sodium influx occurs before the ions diffuse away, the depolarizing effect on membrane potential would be additive.

​Figure 5.16. Summation of graded potentials​.​

Opening up a single potassium channel would create an IPSP. If more potassium channels on a nearby region of the plasma membrane are opened at the same time, an even greater hyperpolarization would be produced.

However, just because synaptic potentials can be summed doesn’t always mean that the change in membrane potential is amplified. For example, opening a ligand-gated sodium channel (EPSP) and a ligand-gated potassium channel (IPSP) at the same time would produce summation, but this would have a cancelling effect instead of an amplifying effect.

​Consider for a moment that every neuron inside your body forms an average of seven thousand synapses! This means that there are hundreds or thousands of synaptic potentials being produced by the dendrites, and traveling toward the axon at any moment – both EPSPs and IPSPs! This allows for a large gradation in the change produced in membrane potential, and means that in addition to what we have discussed already, one major function of the soma is integration. In other words, this region of the cell functions a lot like a supercomputer – summing EPSPs and IPSPs on an unimaginable scale to calculate the net change in membrane potential. The product of this calculation will determine whether the cell will produce enough of a depolarization to reach the threshold required to initiate an action potential, and relay the message it has received to another cell. Synaptic potentials that do not depolarize membrane potential enough to reach threshold are known as subthreshold, whereas those that are strong enough to reach threshold are referred to as suprathreshold. These two terms are commonly used to describe the all or none principle of the action potential – it is produced in response to a suprathreshold stimulus, or not at all, and it does not change its characteristics with increasing or decreasing amounts of stimulation.

5.8 Action Potentials Result from Suprathreshold Stimuli

​Unlike the dendrites and soma, which contain large numbers of ligand-gated ion channels, the axon contains voltage-gated ion channels. Voltage-gated channels are gated by a change in membrane potential. One way to think about this difference is that the axon is more in tune with the local electrical changes taking place around it, whereas the dendrites and soma are more concerned with the abundance of neurotransmitter being released. This ability of voltage-gated channels is what creates the action potential. The axon initial segment, also known as the axon hillock or trigger zone, contains the highest density of voltage-gated channels within the entire neuron – which is why the action potential is generated in this region.

Unlike graded potentials, which are decremental, the changes in membrane potential produced by an action potential have identical characteristics (e.g., amplitude, frequency) down the length of the axon. This is possible because an action potential produces identical changes in ion permeability throughout the length of the axon. A typical action potential is represented in the diagram below.

​Figure 5.17. The major steps of a representative action potential.​
  • The action potential begins at resting membrane potential.
  • The neuron depolarizes from resting membrane potential to reach threshold.
  • Membrane potential continues to become more positive after threshold is reached. This is the depolarization phase.
  • Eventually, depolarization reaches its maximum. This is known as the peak phase.
  • After the peak, membrane potential becomes more negative at it returns toward resting membrane potential. This is referred to as the repolarization phase.
  • The membrane potential becomes more negative than resting membrane potential. This is known as the hyperpolarization phase.
  • The membrane potential then becomes more positive, to return to resting membrane potential. This is known as the after-hyperpolarization phase.
Question 5.20

Place the following phases of the action potential in the order that they would occur at the axon hillock:

A

Resting Vm_m

B

Membrane potential stops depolarizing

C

Membrane potential becomes more positive

D

Membrane potential becomes more negative

E

EPSPs are summed

F

Membrane potential is more negative than resting membrane potential

G

Membrane potential becomes more positive to reach resting membrane potential

​The resting membrane potential, as described earlier, is characterized by a high potassium permeability, low sodium permeability, and low chloride permeability. The major contributors to resting membrane potential are leaky potassium channels, which are always open. To address a very common misconception, it’s worth mentioning that all channels that are open at rest remain open. The action potential, like graded potential, will describe only the events that produce a change from resting membrane potential. There are many things still “happening in the background” (e.g., potassium efflux through leak channels, the pumping of sodium potassium by Na/K/ATPase) that are accounted for in the steady state of resting membrane potential.

Question 5.21

Which ion has the greatest permeability at phase 1 on the graph above?

A

Potassium

B

Sodium

C

Calcium

D

Chloride


Question 5.22

What channels create the high permeability in phase 1?


When a depolarizing stimulus is received, membrane potential becomes more positive. At the axon hillock, the depolarizing stimulus comprises the temporally and spatially summed synaptic potentials. If the stimulus is subthreshold, the action potential will not fire; if it exceeds threshold, it will fire.


A ten year old girl who has been otherwise healthy up to this point begins to experience severe dystonia,  a disorder characterized by lack of coordination and control over skeletal muscle.    Her handwriting has become illegible, she is drooling, and her walking gait is very unsteady.   Her neurologist detects no abnormalities in her blood and cerebrospinal fluid.  An MRI has revealed that she has no lesions on her brain.   After a series of failed treatments, her neurologist performs a genetic test revealing a mutated copy of the ATP1A3 gene, which encodes the sodium potassium pump.   With this particular mutation, the pump is not able to operate at the same capacity as a patient with a normal copy of the gene.  The neurologist diagnoses her with Rapid Dystonia Parkinsonism

In The Clinic

How does rapid dystonia parkinsonism impact membrane potential?

A

Resting membrane potential would become more depolarized

B

Resting membrane potential would become more hyperpolarized

C

Resting membrane potential would be unchanged


​The depolarization phase is characterized by rapid sodium entry through voltage-gated sodium channels (Nav). Recall that voltage-gated channels are gated by changes in membrane potential because they have charged amino acids that function as voltage sensors. This process is illustrated for a single voltage-gated sodium channel in the figure below.

Figure 5.18. The three states of the voltage gated sodium channel: Closed (left), Activated (middle), Inactivated (right)​.

​At resting membrane potential, Nav are in the closed state. As membrane potential depolarizes from resting membrane potential toward threshold, the activation gate undergoes a conformational change and begins to open. When threshold is reached, the activation gate is open, which means that the channel is in the open or active state. In the open state, the channel is permeable to sodium ions, and sodium influx causes a rapid depolarization of membrane potential. It’s important to remember that any measurable change in membrane potential is the result of many channel openings – in the case of the voltage-gated sodium channels, however, these channels open through a positive feedback mechanism known as the Hodgkin Cycle. This is because the influx of positively charged sodium ions causes depolarization, which in turn stimulates more voltage-gated sodium channels to open. As sodium permeability continues to increase, membrane potential rapidly depolarizes toward ENa. During this phase, potassium permeability is low, but is steadily increasing as voltage-gated potassium channels (Kv) begin to activate.

Figure 5.19. Conformational changes in a voltage gated sodium channel regulate the pore opening. (a) Closed, (b) After depolarizing subthreshold stimuli, (c) Open, (d) Inactivated.


Congenital insensitivity to pain (CIP) is a disorder characterized by an inability to feel physical pain, and results from mutations in the voltage-gated sodium channels in the sensory neurons that sense pain. The mutation renders the channels non-functional.


5.8.1 ​The Peak Phase

​Like all positive feedback loops, the influx of sodium through Nav is terminated independently of the stimulus. If we think of an ion channel gate as being like a door on a house, then voltage-gated sodium channels also have a second door – like a storm door. During the depolarization phase, both doors are open and sodium ions can enter the cell. During the peak phase, the Hodgkin cycle is terminated by the closing of the screen door- this door is called the inactivation gate. Here’s where things get a bit tricky. Closing the inactivation gate drops sodium permeability to zero, which stops the influx of positive charges. However, the activation gate is still open. Therefore, Nav are now in the inactivated state. They are not closed, because that refers to the activation gate being closed. Inactive channels cannot be opened, so the neuron is incapable of firing another action potential while in this state. This results in the neuron being in the absolute refractory period.

Question 5.23

At resting membrane potential, the activation gate is ______________.


Question 5.24

At resting membrane potential, the inactivation gate is ______________.


Question 5.25

At the peak of the action potential, the activation gate is ______________.


Question 5.26

At the peak of the action potential, the inactivation gate is ______________.


5.8.2 ​The Repolarization Phase

​If you have a good grasp of membrane potential from the previous section of this chapter, then you know that reduced permeability to sodium ions should cause repolarization by itself (because it causes Vm to move away from ENa). However, during this phase, voltage-gated potassium channels also reach their peak permeability. Thus, repolarization is greatly accelerated by potassium efflux. The neuron is still in the absolute refractory period.

Question 5.27

Question 5.27

What would happen to repolarization if the extracellular concentration of potassium was suddenly decreased?

Click here to see the answer to Question 5.27.


5.8.3 The Hyperpolarization Phase

During the hyperpolarization phase, voltage-gated potassium channels are open, even as membrane potential approaches resting Vm. Because more potassium channels are open than at resting membrane potential, potassium permeability is higher than at resting Vm, which causes membrane potential to move closer to EK than it does at rest. The inactivation gate of the voltage-gated sodium channels opens during this phase of the action potential, which makes firing a second action potential possible. However, because the cell is hyperpolarized, it will require a greater stimulus to reach threshold than it did at resting Vm. This is known as the relative refractory period.

5.8.4 ​The After-Hyperpolarization Phase

At hyperpolarized membrane potentials, voltage-gated potassium channels inactivate, which reduces the permeability to potassium (note: leaky potassium channels are still open). This brings membrane potential back to its resting value, where the neuron will be held until the next suprathreshold stimulus is received.

5.8.5​ Action Potential Propagation

​The action potential is initiated at the axon hillock. The action potential must move from the hillock to the axon terminal to pass information to another cell. It is a common misconception that depolarization spreads from the axon hillock all the way to the axon terminals via diffusion alone. Remember that ions enter the cell passively and diffuse away from their point of entry – even in the action potential! Axons can be very long (more than a meter in length) – if we had to rely on diffusion to carry ions from the axon hillock to the axon terminal our nervous system would not be able to function because it would (literally) take days!

​Because membrane potential is a local phenomenon, it is helpful to imagine that the axon is divided into imaginary axon segments. Each segment has sufficient numbers of voltage-gated sodium and voltage-gated potassium channels to produce the action potential in that segment. As a consequence, while EPSPs are required to initiate the action potential at the hillock, it is actually the Hodgkin cycle that allows the action potential to spread down the length of the axon. In essence, the action potential is “recharged” at each segment by the influx of a fresh batch of sodium ions. In a segment that has just depolarized, voltage-gated Na+ channels are in the refractory period. As a result, the action potential cannot propagate backwards, since only the forward membrane segment is at resting membrane potential and has closed Nav. The propagation of the action potential is similar to lighting a fuse. At any point in time, there is a part of the fuse actively burning, a part that has just burned and cannot be re-burned, and a part that has not yet burned. If the action potential was initiated in the midpoint of the axon, it could spread in both directions, just like a fuse would burn in both directions if lit in the middle.

Figure 5.20. ​The axon potential propagates between axon segments through local current flow (sodium in, potassium out).

The speed of action potential propagation is important, since it determines how fast information can be relayed from one body structure to another. Two major factors influence the speed of action potential propagation:

1)The Axon Diameter

​Action potentials travel faster through wider axons than narrow axons. The movement of positive charge through the cell interior is dependent on the resistance to diffusion through the middle of the cell interior and along the cell length. This increases the movement of positive charge along the axonal membrane, and the speed of the action potential propagation. Many animals, like the giant squid, exploit this axonal membrane property to increase propagation velocities by having neurons with giant axons. Generally speaking any “pipe”, whether it is an axon, a blood vessel, an airway, or a small intestine, will experience an increase in “flow” (in this case, of charge) in response to an increase in radius. When you are putting out a fire, do you want to use a garden hose, or a fire hose?

2) ​Myelination

​If you have ever attempted to charge your cell phone using a frayed charging cable, then you will understand the importance of myelination, which is another means by which conduction velocities can be increased. Myelin is produced by specialized cells known as Schwann cells and oligodendrocytes. Schwann cells and oligodendrocytes extend their cell membrane to wrap tightly around the outside of the axonal membrane. The cytoplasm of the Schwann cells or oligodendrocytes is squeezed out, leaving only layers of lipid bilayer. The cell membrane that surrounds the axon is known as myelin. Myelin acts as an electrical insulator by increasing electrical resistance by a factor of 5,000, and no current can flow out from a myelinated axon segment. Myelinated axon segments are known as internodes. Between internodes there are non-myelinated gaps. These gaps, known as nodes of Ranvier, are the sites where the action potential is recharged. These nodes dramatically increase the speed of action potential propagation along the axonal membrane. The speed of propagation is increased because it takes less time for positive charge to diffuse along the inside of the cell membrane than it does to open voltage-gated Na+ channels. This process is sometimes referred to by the misnomer saltatory conduction because the action potential appears to be jumping from node to node. However, the action potential does not actually “jump” – current always flows through the axon!

​Figure 5.21. Myelination increases the conduction velocity in comparison to an unmyelinated neuron of equivalent diameter.​

Question 5.28

Question 5.28

How does the density of voltage-gated sodium channels in the internode compare to the node?

Click here to see the answer to Question 5.28.

5.9 Presynaptic and Postsynaptic Physiology

​After the last membrane segment of the axon depolarizes, the action potential enters the axon terminal. The axon terminal is responsible for relaying the message to the post-synaptic cell through the synapse. The formation of synapses between pre-synaptic and post-synaptic cells is a highly dynamic process that occurs throughout life. In fact, the strength and number of synapses is thought to be a key determinant of neuroplasticity, and plays a large role in learning, memory formation, and nervous system development. Synapses can be either electrical or chemical.

5.9.1 Chemical Synapses

When two neurons form a chemical synapse, the pre-synaptic and post-synaptic membranes have significant differences in their structure and function (we have already discussed axodendritic synapses above). The pre-synaptic cell is characterized by the presence of vesicles filled with neurotransmitter and other chemicals. These vesicles are close to the pre-synaptic membrane in the synapse. Empty vesicles are filled with neurotransmitter in the axon terminal. These “full” vesicles then dock with proteins known as SNAREs (soluble N-attachment protein receptor) proteins. Calcium entry from the extracellular fluid, through voltage-gated calcium channels, allows the vesicles to fuse with the pre-synaptic membrane and release neurotransmitter into the synaptic cleft. The empty vesicle is recycled within the cell and refilled with neurotransmitter with the whole process occurring in less than 60 seconds.

​​Figure 5.22. The axon terminal is the distal region of the axon, and contains vesicles filled with neurotransmitter​.

The length of time that neurotransmitter exists within the synaptic cleft is dependent on the rate of its release from the pre-synaptic membrane, its re-uptake into the pre-synaptic cells, and its enzymatic breakdown within the synaptic cleft. In many synapses, transport proteins exist in the pre-synaptic membrane that rapidly re-uptake the released neurotransmitter back into the pre-synaptic membrane. In other synapses, enzymatic activities in the pre-synaptic or post-synaptic membrane rapidly degrade the neurotransmitter. The length of time that neurotransmitter is present within the synapse affects its interaction with its post-synaptic membrane receptor. This length of time is typically very short. If the time is extended by the use of external chemical agents (e.g., hallucinogenic agents like LSD), the neurotransmitter will continue to stimulate or inhibit the post-synaptic cell. In the case of LSD, the continued presence of serotonin (a neurotransmitter) within the synapse leads to auditory and visual hallucinations.

Neurotransmitters

Many substances have been identified as neurotransmitters and many others are suspected of acting as neurotransmitters. A neuron can release more than one neurotransmitter from the same vesicle.

Neurotransmitters can be amino acid derivatives, peptides, proteins, amines, gases, and other chemical ligands. As we described earlier in the chapter, neurotransmitters can either stimulate or inhibit post-synaptic cells depending on the characteristics of their postsynaptic receptors. For example, GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the brain; glycine is the main inhibitory neurotransmitter in the spinal cord. Glutamate (90% of the synapses in the human brain), acetylcholine, dopamine, and norepinephrine are the major excitatory neurotransmitters.

Many common pharmaceutical and illicit drugs mimic the effects of neurotransmitters. Agonists are chemicals that can act like neurotransmitters at the post-synaptic cell membrane and stimulate a receptor. Antagonists are chemicals that block the effects of neurotransmitters by inhibiting the receptor. 

5.9.2​ Electrical Synapses

The connection between a neuron and their targets can sometimes occur through specialized gap junctions. Gap junctions allow small molecules and ions to pass easily from the cytosol of one cell to the next (in both directions). When a current arrives at the pre-synaptic side of an electrical synapse, the current spreads, because of the flow of ions, passively across the gap junction. ​The gap junction allows the action potential in one cell to move rapidly into the other, without the delay inherent in chemical synapses. Electrical synapses are fast but cannot be modulated (changed), so they only occur where speed is paramount. Electrical synapses are found in cardiac muscle and in smooth muscle where it is important to coordinate the activities of a large number of cells. Because the current flows in both directions (bidirectional communication), they do not have dedicated pre-synaptic and post-synaptic membranes (both cells can function as either pre-synaptic or post-synaptic cells).

Question 5.29

What topic did you understand the least from this chapter? Explain. (Remember that we are looking for what you understood the least and not necessarily something that you didn’t understand.)


5.10 In-Chapter Feedback​​

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5.11 Answers to Discussion Questions

Answer to Question 5.27

Repolarization would take place more quickly, because there would be a larger concentration gradient for potassium under these conditions.

Click here to return to Question 5.27

Answer to Question 5.28

The density of voltage-gated sodium channels is less in the internodes because of the electrical insulation that comes from myelin. Essentially, it takes fewer channels to produce the same effect.

Click here to return to Question 5.28

5.12 Image Citations

[1] Image courtesy of Dr. Macro in the Public Domain.

[2] Image courtesy of Lead holder under CC BY-SA 3.0.

Cells that are able to send and receive electrical signals.
Having different homeostatic set-points for a substance in two different regions of the body or cell.
Thinking back to our earlier discussion of cell structure and function, recall that the plasma membrane is semi-permeable. The arrangement of amphipathic [POPUP: Having both polar and non-polar regions.] phospholipids into a bilayer prevents most substances from being permeable without the help of channels and transporters.
Three-dimensional structure.
Attraction or repulsion based upon charge.
The unit used to describe the difference in potential between two compartments.
The equilibrium potential for potassium becomes more positive, which causes resting membrane potential to become more positive. This causes excitable cells (like neurons and the heart muscle) to be held in a depolarized state indefinitely.
Convert one form of energy into another form.
The majority of protein synthesis takes place within the soma – but all regions of the neuron are important for carrying out its function. Proteins synthesized in the soma may include ion channels, transporters, signaling enzymes, and neurotransmitters that are needed in more distal portions of the cell (e.g., the axon terminal), and therefore must be transported anterograde.
Non-neuronal cells that are located in the nervous system.
A change in membrane potential produced on the post-synaptic membrane.
A transient change from resting membrane potential that decreases in intensity over time and distance.
A change from resting membrane potential that is maintained at constant intensity over time and distance.
A synapse formed between the axon terminal of a pre-synaptic cell, and the dendrites of a post-synaptic cell.
Reduce gradually over time or distance.
Individual channels can be activated repeatedly over a short period of time.
Channels that are physically close together can be opened at the same time.
The membrane potential required to start an action potential.
An action potential either occurs, or does not occur. There is no gradation.
A gate that determines whether the voltage-gated sodium channel is in the open or closed state.
A positive feedback loop where voltage-gated sodium channel activation leads to activation of more voltage-gated sodium channels.
The time when an action potential cannot be fired even if the cell receives a suprathreshold stimulus.
A period where a larger than normal stimulus is required to initiate an action potential.
Coating axon segments with a myelin sheath.
Long-term physical and chemical changes that influence neuron and brain function.