August 1, 2004

Wired for Much More than Sound–Neurons and How They Work

Part II: The Transfer

Remember in last month's column I described a scene in which you were walking down a dark alley when you were suddenly attacked. Your immediate reaction was to wrench yourself free from your assailant and run for safety. In order for you to be aware of your attacker's grasp and be able to escape, you needed your neuromuscular system to be in proper working order. The sensory receptors for touch, pressure, and pain, would allow you to detect the presence of your attacker by sending nerve messages to the sensory region of the brain. In response to this insult the motor region of your brain would then send out nerve messages to your muscles in order for you to take evasive action.

In considering how nerve cells (also called neurons), allow us to be able to detect our environment, react, and interact within it, we considered three aspects of neuron function. The first was the initiation of a nerve impulse. In the scenario described above, this would be accomplished by the sensory receptors in the periphery and the motor strip in the brain. How some sensory receptors are able to convert physical stimuli, such as touch, pressure, and light waves, into messages that can be interpreted by the brain, will be dealt with in upcoming columns.

The second item was consideration of how the neuron is able to pass the impulse on from where it is first initiated to where it needs to go. Looking at the scene above this would entail explaining how the initiating sensory neuron or the motor neuron from the brain would be able to send the impulse down its axon. This was discussed in last month's column. I suggest that you may want to review "Wired for Much More than Sound-Neurons and how they Work-Part I-The Impulse" before continuing since everything from here on is built on the information from last month's column.

The final piece of the puzzle that needs explaining is how the neuron is able to transfer the impulse of information on to where it is needed for function. Once again, in considering the attack on your person in the dark alley as described above, once the impulse from the sensory receptor travels down the initial neuron, if it can't be transferred to other neurons so that the message can be sent to the brain, then nothing will have been accomplished.

Similarly, once the motor strip neuron initiates an impulse, the message needs to be able to be transferred to other motor neurons and eventually to muscle cells in order for proper evasive action to occur. If either the sensory or motor system is incapable of transmitting the proper messages then they will have failed in their mission and the very survival of a multi-system organism with a complex body plan will be held in the balance. The transfer of the nerve impulse to other nerve cells or muscle tissue is what this column will discuss.

Review
Recalling some of the specifics regarding neuron function from last month's column:

1. The neuron has a resting membrane potential of -70mV (milliVolts). This is related to the fact that the main positively charged ion inside the cell is K+ (potassium), and the main positively charged ion outside of the cell is Na+ (sodium). There are proteins within the plasma membrane which act as K+ and Na+ ion channels that on opening allow K+ to go out of the cell and Na+ to go into the cell. In the resting state, more of the K+ ion channels are open than the Na+ ion channels so that more K+ has left the cell than Na+ entering, thereby allowing for an overall negative resting membrane potential being present. In the neuron the inside of the cell tends to be more negative than the outside of the cell by a value of 70mV. Therefore it said that the resting membrane potential of the neuron is -70mV.
2. The initiation of an impulse within the axon of the neuron, after adequate stimulation, is directly related to its impact on opening more and more Na+ ion channels which allows Na+ ions to enter the cell thereby reversing the polarity of the membrane from -70mV to +40mV. This is called the depolarization of the membrane and it produces what is known as the action potential. The Na+ ion channels are voltage-gated, in that, as the membrane potential becomes less and less negative, more and more of them open up, thereby allowing a maximal amount of Na+ into the cell and depolarization to take place.
3. The impulse is able to conduct along the axon, away from the initiating region, as the depolarizing wave causes similar voltage-gated Na+ ion channels nearby to open up and likewise cause the same reversal of polarity.
4. After the depolarizing wave is started and passes along the axon, the neuron is able to repolarize to its initial resting membrane potential of -70mV. The voltage-gated Na+ channels start to close down as the membrane potential peaks at +40mV and voltage-gated K+ channels open up to let K+ leak out of the neuron to reverse the effects of Na+ having entered. So, the Na+ and K+ ion channels are regulated by the changing membrane potential and they open and close respectively in such a way that allows for depolarization and repolarization. Thus, the neuron is not only able to transmit an impulse by way of the depolarization wave, but is also able to prepare itself to do it again by way of repolarization.
5. Although the resting membrane potential of the neuron has been returned to its original value of -70mV, it has been at the expense of allowing Na+ ions into the cell and letting K+ ions out. Continued depolarization-repolarization of the neuron would ultimately deplete the cell of its much needed K+ level. In order to maintain the proper balance of K+ ions inside the cell, there exists a sodium-potassium pump which needs energy to pump Na+ out of the cell and bring K+ back in, against their concentration gradients It has been demonstrated that the sodium-potassium pump is necessary for continued neuron function.

The Synapse
Now if you've digested what I've described above and familiarized yourself with the figures from last month's column, let's go ahead and discuss what happens next. How exactly does the neuron transfer the impulse of information on to another neuron or muscle cell? Remember now, the impulse is coming down the axon toward its numerous nerve terminals. Across from the nerve terminals are the nerve or muscle cells that are waiting for the message. In between them is a space called the synaptic cleft, which is about 20 nm (nanometers) in width. Think of it like the English Channel, except the distance between Dover and Calais is now only about one millionth of an inch. (see Figure 1)

The axon bringing in the message is known as the presynaptic neuron and the membrane of the nerve or muscle cell receiving the message is called the postsynaptic membrane. Within the nerve terminals of the presynaptic neuron are numerous synaptic vesicles that contain chemicals known as neurotransmitters. Many different neurotransmitters exist within different neurons. For example, acetylcholine is the neurotransmitter that is released by motor neurons in order to activate skeletal muscle cells. And dopamine, serotonin, norepinephrine, and glycine, are examples of neurotransmitters that are involved in synaptic transmission in the central nervous system.

Some of these neurotransmitters attach themselves to receptors that directly affect ion channels on the post-synaptic membrane. Others attach themselves to membrane bound enzymes which when activated causes an intracellular rise in a messenger chemical which ultimately results in a change in post-synaptic cell metabolism For the purposes of this column I will be focusing on the former mechanism only.

The actual release of the neurotransmitter is dependent on the change in the membrane potential of the pre-synaptic neuron. As the depolarization wave enters the nerve terminal, this activates voltage-gated Ca++ (calcium) ion channels which open up, allowing Ca++ ions to enter the cell. The elevation of Ca++ ions into the nerve terminal then acts as a signal and causes the synaptic vesicles to release their contents of neurotransmitters into the synaptic cleft. (see Figure.1).

As noted above, one common example of how neurotransmission takes place is that the neurotransmitter moves across the synaptic cleft and binds to specific receptors on the post-synaptic membrane which opens specific ion channels. These are known as chemical, or ligand-gated, ion channels (see Figure.2).

This usually causes the membrane potential of the post-synaptic cell to change by becoming more or less negative. For example, the neurotransmitter may be able to activate Na+ ion channels, allowing Na+ to enter the cell, and the post-synaptic membrane may start to depolarize (become less negative). If the post-synaptic cell is a neuron and enough activation occurs, this may result in that neuron totally depolarizing and sending the impulse down its axon on to another nerve or muscle cell. If the post-synaptic cells are muscle cells, enough activation may result in depolarization of the muscle membrane eventually resulting in contraction of the muscle. (the way this happens will be discussed in next month's column).

Similarly, the neurotransmitter released by the pre-synaptic neuron may bind to receptors on the post-synaptic neuron which open up negatively charged chloride (Cl-) ion channels instead of positively charged Na+ ion channels. Since the concentration of chloride outside of the cell is much higher than inside the cell, this will result in Cl- entering the cell through the opened ion channels resulting in the post-synaptic membrane becoming more negative and therefore rendering it less likely to be depolarized. This action will have, in effect, allowed the pre-synaptic neuron to have inhibited the post-synaptic cell by way of its neurotransmitter release into the synaptic cleft.

So one can readily see that neuromuscular function at the biomolecular level is indeed very complex. Specific pre-synaptic neurons secrete specific neurotransmitters into the synaptic cleft at the signal of Ca++ ions entering the nerve terminals through voltage-gated Ca++ ion channels upon depolarization of the cell membrane.

The neurotransmitter then crosses the synaptic cleft and locks on to specific chemical-gated ion channels which causes them to open and allow the specific ions to enter the post-synaptic cell resulting in either excitation or inhibition. But there's still more to consider. Let's look at what happens when a motor neuron sends a message to muscle tissue and tells it to contract.

Acetylcholine and Neuromuscular Transmission
Acetylcholine is the neurotransmitter for neuromuscular function. When it is released by a motor neuron it is taken up by the acetylcholine receptors on the postsynaptic membrane of the muscle cell. (fig.1) By locking onto these chemical-gated positive ion channels (see fig. 2), this allows positive ions like Na+ to enter the muscle cell. This leads to the depolarization of the muscle membrane which eventually results in muscle contraction. So one can now see how the nervous system is able to directly control muscle function.

However, it is important to recognize that the duration of the effects of acetylcholine on the muscle cell is limited by three main factors:

1. Acetylcholine is rapidly broken down by the enzyme acetylcholinesterase
2. Acetylcholine is taken up by the presynaptic neuron and other nearby cells
3. Acetylcholine gradually washes away from the postsynaptic cell where it can then be enzymatically broken down or taken up by other cells

One of the key aspects of neuromuscular function is control.. If you turn something on, you also have to be able to turn it off in order to maintain control. Without the ability to limit the effects of acetylcholine by way of enzymatic breakdown, re-uptake by nearby tissue, and diffusion away from the myoneural synaptic cleft, this would allow acetyl-choline to have an unduly prolonged effect.

What do you suppose would result from this excessive activity of acetylcholine on muscle tissue? Think about it. Once the acetylcholine has been released, it will cause depolarization of the muscle membrane and the muscle will contract. What if the acetylcholine keeps hanging around and won't go away?

Initially the muscles would continue to contract without the ability to relax. This would eventually result in generalized muscle cramping, spasms and seizures. Then, after that, generalized paralysis would occur because the muscle cell membrane, under the effects of prolonged acetylcholine activity, would not be able to repolarize in readiness to allow for renewed contraction.

Without acetylcholine, its chemical-gated receptors on the postsynaptic muscle cell membrane, and the ability to limit its effects, particularly by acetylcholinesterase activity, the body would not be able to sustain any neuromuscular function and we would die.

Let's look at a few examples of medical illnesses or situations that directly result from defective neurotransmitter release, reception and breakdown.

Pathophysiology of Neuromuscular Dysfunction Resulting in Death
Botulism: a condition in which bacteria form a neurotoxin that blocks the release of acetylcholine thereby resulting in progressive paralysis and death. This poisoning syndrome demonstrates what would happen if acetylcholine did not exist: death!!

Curare (arrow poison): neuromuscular blocker that attaches itself to the chemical-gated receptor of the ion channel on the plasma membrane of the muscle cell without stimulating it. This renders the ion channel being incapable of activation by acetylcholine, resulting in paralysis and death. This lesson demonstrates what would happen if the acetylcholine receptors on the post-synaptic muscle membrane did not exist: death!!

Acetycholinesterase inhibitors (e.g. insecticides): toxic exposure to these agents results in the muscle membrane being continuously depolarized as described above. This, at first, excites the neuromuscular system, and then paralyzes it, resulting in death. This shows what would happen if adequate supplies of acetylcholinesterase did not exist: death!!

Myasthenia Gravis: This is an auto-immune disease in which the body makes antibodies that attach to the acetylcholine receptors on the muscle cell membrane, destroying them, or rendering them incapable of activation. This results in progressive weakness and eventually death. This chronic disease once again demonstrates for us the importance of having an adequate supply of functioning acetylcholine receptors on the post-synaptic muscle membrane and what happens without them: death!!

Questions for Macroevolution
I hope that you can now understand how a neuron can send an impulse down its axon and release a neurotransmitter from its nerve ends which can directly affect another neuron or muscle cell resulting in a necessary function for the body. Given this understanding and the added information afforded by the pathophysiology of neuromuscular dysfunction resulting in death, let us consider the theory of macroevolution, with its step-by-step mechanics, in order to see if such a theory makes any sense.

To the questions from last month's column which involved:

• the development of specific ion channels (Na+ and K+), allowing for the neuron to have a resting membrane potential of -70mV and thereby being able to be depolarized
• the voltage regulation of these Na+ and K+ ion channels in such a way that allows for the controlled depolarization and repolarization of the neuron membrane, which affords it the ability to transmit an impulse and then be ready to do it again
• the presence of the energy-dependent sodium-potassium ion pump, which is needed to maintain the proper concentration of K+ inside the neuron, thereby allowing for repetitive neuron function after repolarization of the membrane potential back to its resting state

We now add:

• the formation and presence of adequate amounts of specific neurotransmitters within vesicles located in the axon terminals of specific nerves for appropriate neuromuscular function
• the presence of voltage-gated Ca++ ion channels which open on depolarization of the axon terminal membrane allowing Ca++ to enter the nerve cell
• the ability of the vesicles to release adequate amounts of neurotransmitters into the synaptic cleft triggered specifically by the increase of Ca++ ions in the nerve terminals
• adequate neurotransmitter destruction by specific enzymes, which allows the post-synaptic muscle membrane to repolarize and without which proper neuromuscular function could not occur
• the presence of chemical-gated ion channels (see fig.2) and other neuro-receptors on postsynaptic nerve and muscle membranes that are capable of being activated by a specific neurotransmitter which results in a specific function, without which proper neuromuscular activity and coordination could not occur
• the adequate re-uptake of released neurotransmitter or its breakdown products into the presynaptic neuron in order to be able to limit the neurotransmitter's effect on the postsynaptic cell and provide the presynaptic neuron with the building blocks for new neurotransmitter formation

All nine of these components are necessary for properly controlled neuromuscular function, and in effect, for our survival on earth. If this system developed one step at a time, by small changes, as macroevolution proposes, then one must ask oneself which component came into existence first, what purpose did it serve that organism without the rest, and which component came next until the system as we know it existed?

Simply by looking just at acetylcholine, its metabolism, and how it exerts its effect, one can readily see that this would seem to be an impossible task. Medical science can show conclusively that not only is acetylcholine absolutely necessary for proper neuromuscular function, but so is the acetylcholine receptor on the postsynaptic muscle membrane. In addition, because the effect of unopposed acetylcholine on the postsynaptic muscle membrane has been demonstrated to render it in a state of constant depolarization and thereby prevents continued neuromuscular transmission, acetycholinesterase, the enzyme that limits acetylcholine's activity within the synaptic cleft, has also been demonstrated to be absolutely vital for proper neuromuscular function .

It is evident that all three of these factors must have come into existence at the same time in order to allow for the proper function of nerves and muscles which affords us the ability to survive on earth. Macroevolution must explain, not only how an organism could have developed the ability to produce acetylcholine and its controlled release mechanism within the motor neuron, but also what useful purpose it may have served without the presence of both, acetylcholine receptors on the ion channels of the post-synaptic cells, and the enzyme acetylcholinesterase. Think about it! How could controlled neuromuscular action have taken place in such an organism to allow for survival, knowing what we know about how this system actually works?

So! Do these facts point the mind to accept macroevolution and its step by step mechanics as being an absolute truth of Nature? Or do they point us to the distinct possibility that this system just may have been intelligently designed? Which is more reasonable? Which is more plausible and consistent with our own experience and understanding of how complex systems come into existence and how they function?

Just consider the myriad of human invention. Yet, the way in which one's own body is able to be alive here on earth points to a complexity and beauty that is infinitely greater than all of human creativity.

As a physician, I am daily called upon to make decisions that affect my patients, based on numerous bits of information that ultimately requires analyses. After considering the information set before me, and provided for your perusal in this and previous columns, and more to come, for my part, I choose the latter diagnosis of intelligent design, until such time that science can adequately answer the questions that I have raised here in these columns. For who, on encountering the proverbial watch in the field, would for even a moment, consider that it had come about by the random forces of nature? Not many people I venture. Yet so many people have come to uncritically believe in macroevolution despite the contradicting evidence contained within the biomolecular basis of life and the pathophysiology of disease, dysfunction and death.

Next month, as promised, we'll look at what happens to make muscles contract. If you've understood these last two columns, you're already half-way there. See you then in: Wired for Much More than Sound: Part III: Muscle Cells and How they Contract

Dr. G.

Howard Glicksman M. D. graduated from the University of Toronto in 1978. He practiced primary care medicine for almost 25 yrs in Oakville, Ontario and Spring Hill, Florida. He recently left his private practice and has started to practice palliative medicine for a Hospice organization in his community. He has a special interest in how the ethos of our culture has been influenced by modern science’s understanding and promotion of what it means to be a human being.

Copyright 2004 Dr. Howard Glicksman. All rights reserved. International copyright secured.
File Date: 8.01.04