Molecular Mechanisms of Action Potential Generation, part 2

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From the course by Duke University

Medical Neuroscience

1263 ratings

Duke University

Medical Neuroscience

1263 ratings

Medical Neuroscience explores the functional organization and neurophysiology of the human central nervous system, while providing a neurobiological framework for understanding human behavior. In this course, you will discover the organization of the neural systems in the brain and spinal cord that mediate sensation, motivate bodily action, and integrate sensorimotor signals with memory, emotion and related faculties of cognition. The overall goal of this course is to provide the foundation for understanding the impairments of sensation, action and cognition that accompany injury, disease or dysfunction in the central nervous system. The course will build upon knowledge acquired through prior studies of cell and molecular biology, general physiology and human anatomy, as we focus primarily on the central nervous system. This online course is designed to include all of the core concepts in neurophysiology and clinical neuroanatomy that would be presented in most first-year neuroscience courses in schools of medicine. However, there are some topics (e.g., biological psychiatry) and several learning experiences (e.g., hands-on brain dissection) that we provide in the corresponding course offered in the Duke University School of Medicine on campus that we are not attempting to reproduce in Medical Neuroscience online. Nevertheless, our aim is to faithfully present in scope and rigor a medical school caliber course experience. This course comprises six units of content organized into 12 weeks, with an additional week for a comprehensive final exam: - Unit 1 Neuroanatomy (weeks 1-2). This unit covers the surface anatomy of the human brain, its internal structure, and the overall organization of sensory and motor systems in the brainstem and spinal cord. - Unit 2 Neural signaling (weeks 3-4). This unit addresses the fundamental mechanisms of neuronal excitability, signal generation and propagation, synaptic transmission, post synaptic mechanisms of signal integration, and neural plasticity. - Unit 3 Sensory systems (weeks 5-7). Here, you will learn the overall organization and function of the sensory systems that contribute to our sense of self relative to the world around us: somatic sensory systems, proprioception, vision, audition, and balance senses. - Unit 4 Motor systems (weeks 8-9). In this unit, we will examine the organization and function of the brain and spinal mechanisms that govern bodily movement. - Unit 5 Brain Development (week 10). Next, we turn our attention to the neurobiological mechanisms for building the nervous system in embryonic development and in early postnatal life; we will also consider how the brain changes across the lifespan. - Unit 6 Cognition (weeks 11-12). The course concludes with a survey of the association systems of the cerebral hemispheres, with an emphasis on cortical networks that integrate perception, memory and emotion in organizing behavior and planning for the future; we will also consider brain systems for maintaining homeostasis and regulating brain state.

From the lesson

Neural Signaling: Electrical Excitability and Signal Propagation

We now turn our attention from the tangible (human neuroanatomy) to the physiological as we explore the means by which neurons generate, propagate and communicate electrical signals. After exploring those structures in the human brain that are visible to the unaided eye, we must now sharpen our focus and zoom-in, as it were, to the unitary level of organization and function in the central nervous system: to the level of individual neurons and their component parts that are crucial for neural signaling.

Overview of Neuronal Signaling14:32

Ionic Basis of the Resting Membrane Potential, part 114:02

Ionic Basis of the Resting Membrane Potential, part 215:46

Ionic Basis of the Action Potential, part 118:39

Ionic Basis of the Action Potential, part 212:34

Ionic Basis of the Action Potential, part 315:35

Molecular Mechanisms of Action Potential Generation, part 120:36

Molecular Mechanisms of Action Potential Generation, part 29:59

Propagation of Action Potentials20:34

Meet the Instructors

Leonard E. White, Ph.D.
Associate Professor
Department of Neurology, Department of Neurobiology, Duke University School of Medicine; Department of Psychology & Neuroscience, Trinity College of Arts & Sciences; Director of Education, Duke Institute for Brain Sciences; Duke University

So what we've been talking about so far are the molecular structures that

constitute ion channels and this is a way of discharging those gradients that are

essential for generating electrical signals.

Now, let's turn to the molecular mechanisms that are responsible for

establishing those gradients in the first place.

I mentioned when we first introduced this topic that those gradients are

established by ion pumps and ion transporters.

And here we see a variety of pumps and transporters.

Probably the most important that I should emphasize is right over here on the left

hand side of figure 4.9. It's the Sodium-Potassium ATPase.

This is, arguably the most important molecule in the nervous system.

It seems a little ridiculous to even make such a claim, but if it were possible to

identify one molecule of supreme importance this would be it

Sodium-Potassium ATPase. It consumes a significant portion of all

of the energy that is burnt up in the function of a nervous system.

And it's one of the principal reason why the brain requires such a constant and

highly regulated flow of blood to deliver oxygen and glucose the principal

substrates for oxidative metabolism in brain tissue.

There are other pumps besides the Sodium-Potassium ATPase.

As we see here there are pumps for calcium.

There ion exchangers that move sodium and calcium and protons.

There are co-transporters that can take advantage of a concentration gradient for

one ion to transport another and we don't need to get into all of this complexity

at the present time. Rather, what I want to do is consider in

a little bit more detail, the function of.

Our principal pump, the Sodium-Potassium ATPase.

Now, the story of how this function works is the result of a lot of empirical

research that had been done in various ways one can imagine based on our prior

consideration of the action potential that one can study this pump by removing

either sodium or potassium from the solution and asking how these

manipulations might affect pump activity. One might also gain some insight by

depriving that pump of its supply of energy to find out what's happening.

So these kinds of experiments, were done. and what's shown here in figure 4.10 is

an experiment where a, tagged sodium molecule was allowed to flux across the

plasma membrane, due to the activity of this pump.

So sodium was loaded up within a cell and the efflux of sodium which represents the

activity of the pump is measured over time.

So as this experiment unfolds there is some discharge of sodium ions that can be

measured experimentally. And if one removes potassium from the

medium outside of the cell, now there's a sudden drop in the activity that's being

indicated by the efflux of sodium. So this suggests that there must be some

kind of codependency between the Influx of potassium ions into the cell, and the

efflux of sodium. Well, when potassium is restored, and the

fluid's around the cell. Now, the rate of discharge of sodium is

restored. But now, a key experiment is imposed upon

this model system. the energy that's required to drive this

activity is depleted by adding a compound which blocks the synthesis of adenosine

triphospate which is the main energy currency for active cells.

And, as this metabolic, poison, if you will, is introduced, there is a

precipitous decline in the efflux of sodium ions providing strong evidence for

the energy requirement of this transport. When ATP is restored, then there is a

somewhat rapid rise again of efflux of sodium, back towards the rate at which

this experiment was run. So taking these two phases of the

experiment together, we know that there's some kind of co-dependency between the

influx of potassium and the efflux of sodium, and we also know that this

process is energy dependent. So these kinds of experiments have led to

the following model. There is some kind of integral membrane

protein, that constitutes a pump for sodium and potassium.

And this integral membrane protein has enzymatic activity that can cleave ATP

and consume energy in the form of breaking that high-energy phosphate bond.

So, we have good reason to believe that there is a configuration of this protein

that allows for the binding of sodium ions to the exposed cytoplasmic domain

within the central region of this integral membrane protein.

There seems to be a particular stoichiometry to the transport of sodium

and potassium. We think there're likely three binding

sites for sodium ions that are available in this configuration.

And then with the consumption of energy, in the form of cleaving this high-energy

phosphate bond from ATP, there is a conformational change, such that this

protein appears to flip within the membrane.

We don't know exactly how this happens. But it seems to change conformation

allowing these three sodium ions now to be discharged.

On the extracellular face of the membrane, and at the same time, this

conformational change has exposed now binding sites for potassium ions.

Now, with the binding of these potassium ions, the inorganic phosphate is lost,

and the conformational change occurs. And we are restored to the starting

configuration of this protein. And this allows for these potassium ions

now to be discharged and enter the intra-cellular space.

So now this protein is ready to return to its starting position.

In this schema, where sodium ions can aggregate.

So with the consumption of a high-energy phosphate bond, there is a cycle of this

pump that transports 3 sodium ions from inside the cell to outside the cell.

While at the same time allowing for 2 potassium ions to travel from outside of

the cell to the interior. So as this pump churns and burns energy

we establish a concentration gradient with higher sodium ions outside of the

cell compared to inside, and higher potassium concentrations inside the cell

compared to outside. All of this requires energy.

Now, notice the stoichiometry. There's more positive charge leaving the

cell than entering the cell with each turn of a cycle.

From this point of view, we say that this pump activity is electrogenic, that is,

it has the potential to generate a small current.

That current typically is negligible unless we're talking about a very small

compartment where the concentrations of ions might actually change during the

course of a high frequency burst of action potentials.

Such compartments exist in the smallest of our axons we find in peripheral

nerves. So, in such situations as ionic

concentrations might be altered by a burst of action potential activity, pump

activity will increase, more positive charge will leave the cell as a result of

the pump, and the inside of the cell will hyperpolarize.

So that would be the impact of this electrogenic nature of pump activity.

Again, it's typically negligible, except for the very smallest of axons, or the

very tightest of compartments where pump activity can have an impact on the

resting memory potential. Well we can summarize and have an

opportunity to review these mechanisms of pump activity by viewing a animation from

chapter four you can follow this animation.

by navigating to the website that supports our textbook or by clicking on

the hyperlink that you have available to you at the bottom of your tutorial notes.

Well, I hope this has been helpful. Our next tutorial will focus on the means

by which electrical signals can propagate along an axon.

And we will return to some of these concepts related to the structure of ion

channels and pumps when we consider synaptic neurotransmission in forthcoming

tutorials.

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