Department of Physiology: Nerves and Muscles Physiology-Offline information

Tips & Tricks:

To remember the relative distribution of ions across the resting cell membrane, associate Negative with iNside and pOsitive with the Outside.

Flushing a toilet provides a useful analogy for an action potential. Nothing happens while you press the handle, until the water starts to flow (threshold is reached). After that, the amount of water that is released is independent of how hard or quickly you pressed the handle (all-or-none principle). Finally, you cannot flush the toilet again until the tank refills (refractory period).

Endorphins are so named because they act like endogenous (coming from within the body) morphine.

Important Facts about Action Potentials: Very few ions move through the membrane during the action potential. In fact, only about one millionth of the ions available participate in an action potential. There is, therefore, no appreciable change in the concentration gradients for the various ions after one action potential.

Thousands of action potentials can be generated before the concentration gradients for sodium and potassium break down enough to prevent the generation of further action potentials.

The sodium/potassium pump is not required for repolarization. The membrane potential is brought back to resting levels by the continued increased conductance of potassium when sodium permeability has returned to normal.

Graded potential: Action potentials, as we will see in the nervous system module, do not always occur. They require a strong depolarization at the axon hillock to open many voltage-gated Na⁺ channels. Consider a hypothetical situation (shown in the video), where only two voltage-gated channels open to allow some Na⁺ into the cell. In this example, the small number of Na+ ions entering the cells will cause a small depolarization (small buildup of positive charge), but the cell will attempt to maintain its resting membrane potential at –70 mV. The buildup of positive charge, consequently, will affect other ions inside and outside the cell, especially K⁺ and chloride (Cl^–). Since K⁺ has a positive charge, it will leave the inside; at the same time, Cl^– (which is negative) will be attracted into the cell. The movement of both of these ions (K⁺ out and Cl^– in) will repolarize the membrane potential back to normal.

Voltage-Gated Sodium & K Channels: As the name implies, these channel is specific for sodium and potassium and will allow no other molecule through (figure). As already mentioned, these channels have gates that open only when there is a depolarization of the membrane (when the inside becomes more positive). Here is the summary of events (see video):

Depolarization of the membrane occurs (membrane potential becomes more positive/less negative).
Activation gate opens immediately.
Na⁺ flow into the cell, down the concentration gradient.
Inactivation gate closes and Na^+, can no longer flow into the cell; the channel cannot open.
Channel returns to resting configuration (inactivation gate open and activation gate closed).
Channel is now ready to open again.

The voltage-gated K⁺ channels contain only one gate, which opens when the membrane depolarizes. Unlike the Na⁺ voltage-gated channel, these channels do not have an inactivation period (see video). However, they do not open immediately like the Na⁺ voltage-gated channels. In fact, they begin opening when the Na⁺ voltage-gated channels start to become inactivated. This is an extremely important difference between these two channels and, as we will see, is essential to the generation of the action potential.

Here is the summary of events:

Depolarization of membrane occurs (membrane potential becomes more positive/less negative).
After a brief pause, K⁺ voltage-gated channels open (unlike Na⁺voltage-gated channels, which open immediately).
K⁺ flow out of the cell, down their electrical and chemical gradients.
Gate closes and channel returns to resting configuration.
Channel is now ready to open again.

Propagation of the Action Potential down an unmyelinated Nerve: The following steps summarize propagation of an action potential down an unmyelinated axon (video):

Where an action potential exists on the axon, the inside of the membrane is positive (about +35 mV) with respect to the outside because of the Na⁺that have entered the cell.

This positive charge is attracted to and moves toward an area of the membrane next to it that is at rest and has a negative charge; this creates a local current (+ –).

Because of this buildup of the positive charge, the adjacent area of the membrane now depolarizes.

This depolarization triggers voltage-gated Na⁺ channels to open.

Na+, rushes into the cell and depolarizes the region to threshold, creating a new action potential.

By a repetition of this procedure, the action potential is propagated along the membrane.

The best way to picture the action potential propagating down the axon is to think of it like a human wave at a sporting event. One person standing up in the wave triggers his or her neighbor to stand and so on.

Important Facts about Saltatory Conduction: Saltatory conduction is much faster than conduction in unmyelinated fibers. Try the following simple exercise to illustrate this concept:

Walk across the room, placing each foot directly in front of the other with the heel of one foot touching the toes of the other. This is the way that the action potential travels down an unmyelinated fiber. Now, make large leaping steps across the room (taking care not to crash into any furniture). This is how the action potential travels down a myelinated fiber. Which is faster?

Also, like unmyelinated axons, the action potential (shown in red at right, figure) cannot back up the axon because of the absolute refractory period (shown in yellow at right) of the Na⁺ voltage-gated channels. These channels are inactivated in the region behind the moving action potential.

Drugs that affect transmission at the neuromuscular junction:

Drugs acting at the NMJ are used: i) as research tools; ii) therapeutically, as treatments for various neuromuscular disorders; and iii) cosmetically, e.g. ‘Botox’ for ironing-out wrinkling of facial skin. Clinical uses of neuromuscular blocking drugs (functional antagonists) include surgery to increase muscle relaxation under anesthesia. On the other hand, drugs that enhance neuromuscular function (functional agonists) are used clinically to treat diseases like myasthenia gravis or Lambert-Eaton Myasthenic Syndrome (LEMS).

1. Drugs that stimulate the muscle fiber by Ach-like action (agonists) or causing excessive release of Ach: Many different compounds including methacholine, carbachol, and nicotine, have the same effect on the muscle fiber, as does Ach. The difference between these drugs and Ach is that they are not or very slowly destroyed by acetylcholinestrase, so that when moderate quantities applied to the muscle fiber their action persists for many minutes to several hour causing repeated action potentials and consequently a state of muscle spasm. On the other hand, when extreme dose of these drugs are used it causes a state of flaccid paralysis rather than spasm. These effects are due to the fact that prolonged action of Ach or Ach-like drugs causes the Ach-gated ion channels to become desensitized and inactivated. Black widow spider toxin causes an excessive release of vesicles. This causes muscle spasms, cramping pain, and generalized nervous excitation. Drugs belong to this group can also works by blocking presynaptic potassium channels, prolonging the duration of the presynaptic action potential. The prolonged depolarization allows excessive Ca²⁺ ions to enter the terminal through voltage-gated Ca-channels, increasing vesicular fusion rate and hence more Ach release and more EPSP generation.

2. Drugs that stimulate the neuromuscular junction by inactivating acetylcholinestrase: Such as neostigmine, physostigmine, and organophosphates (organophosphates include insecticides and so-called nerve gases, diisopropyl pecialosphates). Therefore, inactivated acetylcholinestrase (by anticholinesterase agents) in the synapses will not hydrolyse the acetylcholine released at the end-plate. As a result, acetylcholine increases in quantity with successive nerve impulses so those extreme amounts of acetylcholine can accumulate and then repetitively stimulate the muscle fiber (spastic paralysis, a state of continual contraction of the muscle). This causes muscular spasm when even a few nerve impulses reach the muscle, which can cause death due to laryngeal spasm.

3. Drugs that inhibit transmission at the neuromuscular junction and cause paralysis of the muscles: This can achieved by drugs that:

Inhibit Ach synthesis,
Prevent filling (storage) of the vesicles with acetylcholine,
Inhibit exocytosis of the ACH-containing vesicles (such Mg²⁺ ions which with compete with Ca²⁺).
Block vesicular release of Ach (such as Botulinus toxin) by preventing fusion of synaptic vesicles with the nerve terminal plasma membrane. Botulinum toxin is produced by the anaerobic bacillus Clostridium botulinum, which may be found in improperly canned food, and is one of the most potent toxins known. This toxin (the agent responsible for botulism) blocks the release of vesicles. This, of course, leads to muscle paralysis (flaccid paralysis, which is a state in which the muscles are limp and cannot contract) and, if the diaphragm becomes affected, can be fatal.
Compete with acetylcholine for the receptor sites of the end-plate membrane at the nerve terminal. Curariform drugs can prevent passage of impulses from the nerve terminal to the end-plate of the muscle fiber. This can be achieved by competing with acetylcholine for the receptor sites of the end-plate membrane, so that the acetylcholine cannot increase the permeability of the acetylcholine channels sufficiently to initiate a depolarization wave.

Neuromuscular Blocking Agents: Neuromuscular blocking agents are very useful in surgery because they relax muscles by paralysing them. This reduces the dose of the anaesthetic agent necessary for surgery. The dose required is just that which will abolish pain. Deeper anaesthesia is required if one has to depend on the anaesthetic to relax the muscles also. A smaller dose of the anaesthetic is safer and quickly rever si ble. However, it is important to remember that neuro muscular blocking agents only paralyse the patient without affecting the ability to feel pain. If the anaesthetic is insufficient even to abolish pain, the patient will suffer from pain and not even be able to indicate it by a reflex movement because he has been rendered completely motionless and speechless by the neuromuscular blocker. Such a patient not only suffers but may also register the rude, crude and lewd banter that sometimes goes on in the operation theatre! Further, patients to whom neuromuscular blockers have been given need artificial respiration. (Why?).

Anatomy of a muscle fiber (see figure): A muscle fiber contains many myofibrils with the components shown. A myofibril has many sarcomeres that contain myosin and actin filaments whose arrangement gives rise to the striations so characteristic of skeletal muscle. Muscle contraction occurs when sarcomeres contract and actin filaments slide past myosin filaments.

Slow-Twitch and Fast-Twitch Muscle Fibers: All muscle fibers metabolize both aerobically and anaerobically. Some muscle fibers, however, utilize one method more than the other to provide myofibrils with ATP.

Slow-twitch fibers tend to be aerobic, and fast-twitch fibers tend to be anaerobic.

Slow-twitch fibers have a steadier tug and more endurance, despite having motor units with a smaller number of fibers. These muscle fibers are most helpful in sports such as long distance running, biking, jogging, and swimming (see figure). Because they produce most of their energy aerobically, they tire only when their fuel supply is gone.

Slow-twitch fibers have many mitochondria and are dark in color because they contain myoglobin, the respiratory pigment found in muscles. They are also surrounded by dense capillary beds and draw more blood and oxygen than fast-twitch fibers.

Slow-twitch fibers have a low maximum tension, which develops slowly, but these muscle fibers are highly resistant to fatigue. Because slow-twitch fibers have a substantial reserve of glycogen and fat, their abundant mitochondria can maintain a steady, prolonged production of ATP when oxygen is available.

Fast-twitch fibers tend to be anaerobic and seem to be designed for strength because their motor units contain many fibers.

They provide explosions of energy and are most helpful in sports activities such as sprinting, weight lifting, swinging a golf club, or throwing a shot.

Fast-twitch fibers are light in color because they have fewer mitochondria, little or no myoglobin, and fewer blood vessels than slow-twitch fibers do.

Fast-twitch fibers can develop maximum tension more rapidly than slow-twitch fibers can, and their maximum tension is greater. However, their dependence on anaerobic energy leaves them vulnerable to an accumulation of lactic acid that causes them to fatigue quickly.

[CLINICAL CORRELATION: About a month before coming to the hospital, a 56-yearold woman noticed she was unable to hold her shopping bag and that her head fell forward when she knelt to tie her shoes. Two weeks later she had to remain in bed and had difficulty sitting up. Her jaw began to droop, she had to hold it up with her hand, and her left eyelid began to droop. Her speech became indistinct when she was excited, swallowing was difficult and ﬂuid sometimes regurgitated through her nose. A few days after admission to the hospital, she developed weakness in the middle and ring fngers of both hands that was increased by excitement and lessened by rest. There was no muscle wasting and tendon reﬂexes were all present. Her masseter muscles showed a decremental response to tetanic electrical stimulation. In the hospital, she was injected with 1 mg of physostigmine. About 1 hour later, her left eyelid elevated, her arm movements were stronger, her jaw drooped less, swallowing was improved, and she reported feeling “less heavy.” The eﬀect wore oﬀ gradually in 2–4 hours. With 1.3 mg the improvement was greater and lasted 4–5 hours. Still greater improvements, lasting 6–7 hours, followed an injection of 1.5 mg but the patient felt faint as if “something were going to happen.” The diagnosis is myasthenia gravis. It is an autoimmune disease that aﬀects about 1 in 5,000 people. The immune system produces antibodies to the nicotinic Ach receptors of the neuromuscular junction and neuromuscular transmission is impaired. With fewer receptors the eﬀects of depression of synaptic transmission lead to a failure of neuromuscular transmission during sustained eﬀort. This fatigability is a characteristic of the disease. Physostigmine is an inhibitor of AChE. In its presence more of the released ACh can interact with the receptor and transmission is more reliable. AChE inhibitors are used to relieve the symptoms of myasthenia gravis. Immunosuppressants, for example, the synthetic corticosteroid prednisone, are used to reduce antibody production. In some cases thymectomy (surgical removal of the thymus) is performed to suppress the immune system. Edrophonium chloride (Tensilon) is a short-acting AChE inhibitor that has been used to assist in diagnosis. Electrical stimulation and testing for circulating antibodies are also used diagnostically].