NMJ: https://www.youtube.com/watch?v=0pdNULe7lw0

Myasthenia gravis: https://www.youtube.com/watch?v=bYGxGdu9MsQ

Muscular dystrophy: https://www.youtube.com/watch?v=DGOmN6rnsNk

Cerebral palsy: https://www.youtube.com/watch?v=csKRVW-HN0E

Bell’s palsy: https://www.youtube.com/watch?v=ic1hKbk4CKc

Huntington’s Disease: https://www.youtube.com/watch?v=nJoS5MOqmH4

The Scene: Santa Monica College, Life Sciences Building, Spring 2020.There is a slow, faint ‘Knock’ on Wissmann’s office door. A sad knock. Wissmann speaks loudly so he can be

heard through the slight opening of the door. The door slowly swings open. Wissmann speaks, “Well Arachidonic Acid, come on in, have a seat, why do you look so sad?”

Arachidonic Acid in a slow, faint, depressed voice utters, “They all just don’t like me, never have, never will.” His emphasis is on the word ‘all’. Wissmann is trying to think fast. To think of the ‘right thing to say’. Wissmann asks, “Why do you even say that? You know, there are a whole heck of a lot of molecules out there, but you are one of the few, one of the chosen ones, that gets to be studied in all the physiology classes. You needn’t feel sad.”

But his words do nothing to change Arachidonic Acid’s mood, as he mutters, “It just gets hard sometimes, always being despised, always being rejected, never even given a chance. And now you won’t be there to defend me in the classroom. You’ve always had my back, as the kids now say. I should be more grateful to you Wissmann for always cajoling, encouraging, threatening your students to not be afraid of me. But now with this online junk you won’t be there to protect me, and I’m now completely depressed. I’ll be hated as always and now ignored and quickly forgotten.”

What could Wissmann do or say? He’d never seen Arachidonic Acid so lifeless, so defeated. Arachidonic Acid knew he was important, very important but without Wissmann by his side he feared that the worst was about to happen. That the worst thing that could ever happen to a biomolecule would come to be, that he’d never be learned about.

Wissmann, being a loyal friend to all the biomolecules and especially empathetic to Arachidonic Acids tendency to always put off people on first meeting, came up with a plan. A good plan. That plan was to write this short story. Arachidonic Acid read it and was pleased. Only time will tell if Wissmann’s plan will work.

Arachidonic acid is a polyunsaturated fatty acid present in the phospholipids (especially phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositides) of membranes of the body's cells, and is abundant in the brain, muscles, and liver.Chemical formula: C20H32O2

I know what a phospholipid is. What enzyme would you use to cut off one or two of the carbon tails? Why of course a phospholipase enzyme. If one of the carbon tails contained in a membrane phospholipid was the 20 carbon Arachidonic Acid fatty acid and it was cut off of the phospholipid molecule with a phospholipase, then you would have a free Arachidonic Acid molecule. They are very friendly, a bit shy, but very useful to you in your body. And for crying-out-loud they are nothing to be afraid of. Simply Arachidonic Acid can be converted into Prostaglandins. There are several prostaglandins so people immediately get confused. So don’t. How does Arachidonic Acid get converted into one of the prostaglandins? By an enzyme called Cyclooxygenase.

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid.

No biggie. COX enzyme converts Arachidonic Acid into Prostaglandin G2. And from there Prostaglandin G2 can be converted to other molecules. For right now, just look at the center of the diagram below.

If you can block the COX enzyme then Arachidonic Acid is not converted into Prostaglandin G2 and everything else it could be turned into. By blocking COX, no more thromboxanes, prostaglandins.

Change of subject. What is inflammation? You do this, do a google search on “what are the 5 classic signs of inflammation?”. Learn them. Are they Spanish or Latin, I dunno, one of you can tell me, but learn them. Sometimes inflammation good, sometimes inflammation not so welcome. So now let’s determine what molecules in the body trigger inflammation. Let’s do the google search together:An inflammatory mediator is a messenger that acts on blood vessels and/or cells to promote an inflammatory response. Inflammatory mediators include prostaglandins, …..So prostaglandins trigger the inflammatory response. See where I am going with this, if you wanted to turn down the inflammatory response you would want to not make prostaglandins and how do you not make prostaglandins? Block their production from Arachidonic Acid by blocking COX! Do your google search and tell me what molecules block COX? You should come up with aspirin and NSAIDS. What does NSAID stand for?

There, no need to fear Arachidonic Acid. Let me mention that there happens to be two forms/types of the COX enzyme, COX-1 and COX-2.

There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining. NSAIDs block the COX enzymes and reduce production of prostaglandins.

Arachidonic acid: https://www.youtube.com/watch?v=gnz841lGa7Q

COX-1 and COX-2: https://www.youtube.com/watch?v=vybF1ZACOyw

https://www.verywellhealth.com/cyclooxygenase-cox-1-and-cox-2-2552188-

Not required but interesting to know: https://www.painedu.org/cox-2-inhibitors/

(first COX discovered to reduce pain; then better COX discovered that had fewer side effects, namely less gastric damage; then shown first exciting studies of this new breakthrough drug for pain not so true; then people taking these drugs were just dropping dead of heart attacks-in very small numbers-but still; so all removed from the market; now this is the part of the story I like-public outcry-we want them back-our arthritis hurts constantly-these the only drugs that take away this constant pain; so FDA puts one back on the market with warnings you could die of a heart attack; public would rather live with risk of heart attack rather than live with chronic pain.)

What else can be used as an anti-inflammatory drug? This diagram will explain:

We already know that NSAIDs will block COX and so the production of prostaglandins and so block the inflammatory response. But notice that ‘glucocorticoids’ block the production of phospholipase A2 which initially cleaves the 20

carbon Arachidonic Acid from the membrane phospholipid. Cool.

Glucocorticoids are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as inflammation. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. Keep in mind the

glucocorticoids also do a lot of other things also. Do not worry, we will not follow (be responsible) for the Lipoxygenase pathway.

Notice in the diagram before the one seen directly above you see the ‘glucocorticoid’ blocking the phospholipase A2. In the diagram directly above it shows the ‘corticosteroids’ blocking phospholipase A2. Are corticosteroids the same as glucocorticoids?

In technical terms, "corticosteroid" refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for "glucocorticoid". ... Cortisol (or hydrocortisone) is the most important

human glucocorticoid. We will talk more about them when we get to the endocrine system.

There you have it. Be nice to Arachidonic Acid.

So, am I ‘opinionated’? No. No way. Well, maybe. But in a well-intentioned way. I say this because we need to explain skeletal muscle cell (remember a muscle cell is called a muscle fiber) contraction. And where does every textbook and video begin? With a diagram of the entire muscle and then looking at smaller and smaller views. I don’t like that approach. Let’s begin with the basics, the molecules that do the contracting and work our way up from there.

Physiology: skeletal muscle fiber contraction

https://www.youtube.com/watch?v=ousflrOzQHc

https://www.youtube.com/watch?v=NfEJUPnqxk0

So, the steps in skeletal muscle fiber contraction:

1) Neurotransmitter released into synapse2) Neurotransmitter binds receptor in membrane of skeletal muscle fiber3) This binding triggers release of calcium from sarcoplasmic reticulum4) Released calcium binds the troponin molecules5) Binding of calcium to troponin causes tropomyosin molecule which is wrapped around the F-actin molecule to

shift ‘out of the way’ so the myosin head can bind to F-actin6) The myosin head binds (using ATP), pivots to pull F-actin in, releases (using ATP) from F-actin7) This bind/pivot/release; bind/pivot/release; etc. continues to contract the entire muscle fiber8) To stop contraction, calcium is removed from the troponin causing tropomyosin to move ‘in the way’, blocking

the myosin head from binding to the F-actin9) The calcium is stored in the sarcoplasmic reticulum.

So, for now, there it is. A nice review from Ana-1. You must understand the position and scale of the myofibril vs what they called the myofilaments which simply are the F-actin and myosin molecules.

Remember that rigor mortis is the condition whereby there is no more ATP (no oxygen, no heartbeat) so no more binding of myosin head to F-actin. But also, no more release of myosin head from F-actin if the two had

bound together before the ATP supply ran out. The muscle fiber stays, after death, contracted.

You’re very observant and you have noticed in these last few diagrams the word, ‘action potential’ listed. You’re saying to yourself, ‘Huh?’ Action potentials are found on neurons. I can draw you a neuron, all the membrane proteins needed, and explain to you in detail how the action potential works…….IN A NEURON!So why do these diagrams explaining skeletal muscle fiber talk about action potentials, or as Paul calls them “APs”. Let me rock your world.Skeletal muscle fibers generate action potentials! Just like a neuron! How come no one ever mentions that?I don’t know. Picture this. A skeletal muscle fiber looks identical to a neuron in its membrane. Well, OK, not completely identical. The skeletal muscle fiber does not have telodendria and does not release neurotransmitters. But my point is that the membrane of a skeletal muscle fiber depolarizes just like a neuron’s membrane depolarizes because both membranes contain all the right membrane proteins to make it happen. On the outside, a neuron and skeletal muscle fiber are identical. What their main difference is that think of a skeletal muscle fiber as a neuron with contractile proteins on the inside. Take a neuron, fill it with actin and myosin and troponin and tropomyosin and you’ve got a skeletal muscle fiber practically.

Remember that a skeletal muscle fiber must contact very, very quickly. The stored calcium must be released very quickly from all the sarcoplasmic reticulum all throughout the skeletal muscle fiber quickly. So how about using a depolarization (they are very fast) to quickly run across the surface of the skeletal muscle fiber as the signal to release calcium from the sarcoplasmic reticulum? Great idea evolution. Give it a try.

So, the signal to release calcium from the sarcoplasmic reticulum is the depolarization, an electrical signal that is fast. So, the sarcoplasmic reticulum must be close to the membrane that has this depolarization occurring over it. This is true. So as the depolarization spreads over the surface of the skeletal muscle fiber, this voltage change needs to trigger the release of calcium from the sarcoplasmic reticulum. All we need to do to make this happen is to add into the membrane of the sarcoplasmic reticulum the membrane proteins that will open to let the calcium out when the voltage just outside changes.Ah ha! A VOLTAGE-DEPENDENT Ca++ GATE.In a skeletal muscle fiber, in the membrane of the sarcoplasmic reticulum are found lots of voltage-dependent calcium gates (VDCa++G). When the surface membrane of the skeletal muscle fiber depolarizes, this voltage change will affect the VDCa++G found within the membrane of the sarcoplasmic reticulum and this gate opens and the calcium diffuses out.

Huh? Calcium diffuses out to bind to the troponin? Why does the calcium diffuse OUT of the now open gate?It diffuses OUT because it diffuses down its concentration gradient. What concentration gradient?More calcium within the sarcoplasmic reticulum than outside the sarcoplasmic reticulum.Why?Because we’ve pumped the calcium into the sarcoplasmic reticulum.How?With CALCIUM PUMPS in the membrane of the sarcoplasmic reticulum.Calcium pumps always pumping calcium into the sarcoplasmic reticulum guarantees high concentration of calcium inside sarcoplasmic reticulum. So, when the calcium gates open, calcium goes out.

See how the T-Tubule (Transverse Tubule) is just an extension of the surface membrane. So as the surface membrane depolarizes, that depolarization signal travels down along the T-Tubule also. And right next to the T-

Tubule is the Sarcoplasmic Reticulum, close enough to detect this change of voltage.https://www.youtube.com/watch?v=QRIxNaMlBsA

https://www.youtube.com/watch?v=n_XAijyu6Ms