The Neuromuscular Junction

by Carlo Raj, MD

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    00:02 Here we’ll take a look at muscle pathology but the focus here will be the neuromuscular junction.

    00:08 So please picture neuromuscular junction.

    00:10 So we have a nicotinic receptor, and in your head, you should be thinking about the presynaptic terminal of the nerve which is then communicating with the motor end plate. In other words, the skeletal muscle.

    00:22 In that presynaptic termina l, we have a vesicle and in that vesicle we have remind me—acetylcholine.

    00:28 So the 2 major neuromuscular junction diseases that we’ll take a look at, myasthenia gravis and myasthenia gravis syndrome.

    00:35 So here’s a young lady, maybe 37 or so, and I told you that at about 8 o’clock in the morning, she’s getting ready for work and she feels okay, but about 11 o’clock or 12 o’clock, she walks in—she’s a secretary for for an executive what have you—and she works in front of a computer, and she has a hard time seeing because the first type of muscle fibers to be affected in myasthenia gravis are of what type again? The fast-twitch called type 2.

    01:02 So if those type 2 muscle fibers are becoming weakened then this patient is having a hard time seeing the screen.

    01:09 Then at about 3 o’clock or 4 o’clock, she is having a hard time getting out of her chair, and you ask yourself, why? Why am I giving myasthenia gravis in the lady? Well, give me one second.

    01:21 Say you have proximal muscle weakness and such that is taking place.

    01:24 The proximal muscles are affected first in myasthenia gravis—difficulty getting out of chair. That’s your presentation.

    01:32 Now, this lady comes in with this presentation, do a chest x-ray, and oh my goodness! You find in the middle of the chest of a 37-year-old female, an enlarged thymus. Excuse me, but you and I as an adult—as a thymus—it should be involuted. It should be gone The education of your T cells has been completed when you are a child.

    01:54 So our thymus should be involuted. [Inaudible 00:01:55] gone.

    01:58 You have a lady adult who has a thymoma no doubt, you’re thinking autoimmune disease. Hence, I’m giving you a young lady.

    02:08 Now could that be a male? Sure, absolutely, but more commonly in a young lady.

    02:13 Now thymoma—let me give you another rule of thumb.

    02:16 Whenever you hear thymoma, then you should be thinking about autoimmune diseases, shouldn’t you? One would be myasthenia gravis, but if there is thymoma and susceptibility to infection, and there’s hypogammaglobulinemia, that’s called Good Syndrome.

    02:31 Or let’s say that you have a thymoma in which the patient now presents with fatigue and tiredness, that’s called pure red blood cell aplasia the only cell to be effected is RBC.

    02:43 From now on, in general, you hear about thymomas, you should be thinking autoimmune diseases.

    02:49 Now what happens now in myasthenia gravis, and why there’s this pattern that I just gave you of tiredness and weakness, is the fact that it is these autoantibodies that are attacking and trying to destroy the acetylcholine receptors on the postsynaptic terminal which is located on the skeletal muscle.

    03:12 If acetylcholine receptors are being destroyed, like target practice—boom! Boom! Boom! Boom! Boom! The more number of receptors that you’re destroying and then you are, cannot then form an end plate potential. In other words, you can’t have a depolarization.

    03:29 If you cannot have a depolarization, how in the world are you supposed to have an action potential? Right? So what are things that you’re going to do to identify [Inaudible 00:03:39] doesn’t mean all receptors have been destroyed.

    03:43 But what if there was a method that you could test and you activate those receptors? If you activate those receptors, then maybe perhaps you will find movement.

    03:53 Keep that in mind. So the weakness has intensified by use.

    03:57 That’s important because you’re going to be comparing myasthenia gravis with what? Lambert-Eaton myasthenia gravis syndrome.

    04:04 So here, in myasthenia gravis, with use, it’s the patient that is feeling tired and recovers upon rest 3 in 100,000 would be the epidemiology.

    04:15 The prevalence, as I’ve told you, would be much more in women because of its autoimmune nature—less than 40 years.

    04:22 If it is a male, by chance, affected greater than 60.

    04:26 Pathogenesis. You have the circulating autoantibodies that are then attacking the acetylcholine receptors, and surgically, there’s a possibility that the thymus may then be removed resulting in a thymic remnant. And by doing so, you are now actually improving the patient’s signs and symptoms.

    04:46 So the thymus is [Inaudible 00:04:47] to type 2 hypersensitivity, autoantibody dependent [Inaudible 00:04:51] toxicity, try and go after those acetylcholine receptors.

    04:58 Association—thymic hyperplasia and thymoma.

    05:02 The pathology here [Inaudible 00:05:04] that the type 2 muscle fibers will be affected first.

    05:10 What kind are these? Fast, white ATPase—lots of it.

    05:17 For example, the ocular muscles.

    05:21 There is absent simplification of the motor end plate, what does that mean? It means that the acetylcholine receptors are being knocked out, and depending as to the severity of the disease, you will still have residual [Inaudible 00:05:33] simplified.

    05:38 Let’s go ahead and take a look at that neuromuscular junction.

    05:41 On the left, is normal.

    05:43 So what is that that you see here? The bulb which is coming down? The bulb that you see coming down or the flask, or whatever you want to call it, it’s the presynaptic terminal, and at the presynaptic terminal, you’ll then notice you have these vesicles.

    05:57 Inside those synaptic vesicles, of course, is your acetylcholine.

    06:02 What then allows for the vesicle to fuse with your presynaptic membrane? Help me out here.

    06:08 Good. Voltage-gated calcium channels.

    06:11 So the voltage-gated calcium channels where are they located? Not on the bottom structure—the bottom structure, what is that? That’s your motor end plate. What does that mean? That’s your skeletal muscle .So we’re trying to have movement—motor end plate.

    06:27 So the voltage-gated calcium channels are on the the presynaptic terminal, on the flask, but then opens up the calcium channel.

    06:37 Voltage coming from where? The axon up above.

    06:42 So the action potential is going to come down the axon, come down through the presynaptic terminal and then open up that voltage-gated calcium channel.

    06:54 The calcium, of course, rushes in allowing for fusion of the synaptic vesicle that you see there.

    07:01 With the membrane, and out then comes whom? The acetylcholine.

    07:07 That acetylcholine is then going to bind to the acetylcholine receptor and open up what kind of channel? [Inaudible 00:07:14] sodium channel.

    07:17 The [Inaudible 00:07:16] acetylcholine and the receptor, of course, being on the skeletal muscle.

    07:22 You have now created what? An end plate potential, and once it hits threshold and have an action potential, it is then going to travel across the wings [Inaudible 00:07:32] that you see here.

    07:35 You have an action potential that is then going across or propagate across the sarcolemma.

    07:42 That’s normal on the left.

    07:44 So what happens in myasthenia gravis syndrome on the right? You’ll notice autoantibodies with the thymic hyperplasia thymoma that is indicated and these are antibodies are then going to attack acetylcholine receptors, making it very difficult for acetylcholine to bind o the receptors, making it almost downright impossible for sodium to come in so that you can have an action potential.

    08:16 If you don’t have an action potential, remind me, does action potentials that should be moving across the flask through the sarcolemma.

    08:24 In physio, remind me, where should it be entering? The T-tubule.

    08:29 Obviously, that picture is not seen here—we’re doing pathology.

    08:32 And once it enters the T-tubule, it is then going to communicate with, remember the [Inaudible 00:08:35] receptors, and we’re going to then bring about a contraction.

    08:42 So that, all important.

    08:44 Junction in communication between acetylcholine receptors, when it’s not happening, you’re not having a contraction.

    08:51 What type of muscle fibers will be affect first? Type 2, your fast-twitch. I gave you the ocular muscles.

    08:58 And what to test that you may want to provide or administer so you can find increase in strength? Do you have any problems with acetylcholine supplies? Nope.

    09:12 The problem is it can’t bond to the receptor.

    09:15 What if you were able to give a drug in which you inhibited the enzyme in that cleft? Remind me what the name of that enzyme and that cleft that breaks down acetylcholine? Cholinesterase. Right? So what if you were able to give a short-acting cholinesterase inhibitor such as edrophonium in which you increased the concentration of acetylcholine in that cleft? It’s possible that the acetylcholine might then linger around and find a receptor that may actually function.

    09:45 Then giving you for that brief moment in time, when you’re given that drug, an increase in strength, and by doing so, you’ve confirmed myasthenia gravis. Haven’t you? Here’s your full picture of normal on the left and on the right what’s happening with a hypersensitivity called myasthenia gravis syndrome.

    10:08 One other thing that I wish to bring to your attention before we move on, what are the names of the receptors on the presynaptic terminal again? Voltage-gated calcium channels.

    10:19 Give me pathology in which those voltage-gated calcium channels will be affected and we’ll discuss coming up? That would be Lambert-Eaton myasthenia gravis syndrome.

    10:28 You will be spending time there.

    About the Lecture

    The lecture The Neuromuscular Junction by Carlo Raj, MD is from the course Muscle and soft tissue: Pathology. It contains the following chapters:

    • The Neuromuscular Junction
    • Structure of the Neuromuscular Junction

    Included Quiz Questions

    1. Myasthenia gravis
    2. Parkinson’s disease
    3. Multiple sclerosis
    4. Alzheimer’s disease
    5. Systemic lupus erythematosus
    1. Acetylcholine
    2. Serotonin
    3. Dopamine
    4. Gamma aminobutyric acid
    5. Histamine
    1. Voltage gated calcium channels
    2. Voltage gated sodium channels
    3. Voltage gated potassium channels
    4. GABA receptor channels
    5. Glycine receptor channels
    1. Thymus
    2. Heart
    3. Lungs
    4. Thyroid
    5. Parathyroid
    1. Good syndrome
    2. Myasthenia Gravis
    3. Rheumatoid arthritis
    4. Pure red blood cell aplasia
    5. Leukemia

    Author of lecture The Neuromuscular Junction

     Carlo Raj, MD

    Carlo Raj, MD

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