Gastric Oxyntic Gland: Control and Regulation – Upper Gastrointestinal Secretion

00:02 Now, how is this secretion of hydrogen ions controlled and regulated? About 40% of it is regulated via the cephalic phase.

00:11 So this is simply the thought of eating and the thought of food starts those gastric juices start flowing.

00:18 About 40% of it is in that format.

00:21 If you know that it’s done through this cephalic phase, you have to think of, “Oh, the parasympathetic nervous system is involved, we’re probably releasing acetylcholine.” If you went that route, you are right, and we’ll go back and talk through that in more specific detail.

00:37 The parasympathetic nervous system involves the vagus nerve, which is cranial nervy number 10, and that directly stimulates acid production.

00:46 One is it can directly stimulate acid production from the parietal cells.

00:50 The second way it can do this is it engages histamine release from ECL cells.

00:57 These are enterochromaffin-like cells.

01:02 Also, ACh stimulates G cells to produce gastrin, and gastrin is another stimulator of hydrochloric acid or hydrogen ion production.

01:13 So it’s interesting to think of that ACh does something directly, and then through to indirect pathways.

01:21 And we’ll talk through why that extra kind of regulation is very important for hydrogen ion production.

01:30 The gastric phase accounts for about 50% of the control and regulation of hydrogen ions.

01:40 And this is primarily done through a process called vago-vagal reflexes.

01:45 So these reflexes are done via stimulation of the vagus nerve, which is cranial nerve number 10, and stimulates more release of acetylcholine.

01:58 The other thing that stimulates from the gastric phase is proteins and peptides, especially amino acids, will help stimulate G cells to release gastrin, and gastrin is a potent stimulator of hydrogen ions.

02:14 Hydrogen ions though do have a negative feedback loop, and that is by stimulating D cells, it will produce somatostatin.

02:22 And somatostatin helps to decrease or stop the hydrogen ion production.

02:29 It’s important process to both engage it and stop it.

02:33 The last phase that we have is the intestinal phase, which only accounts for about 10% of hydrogen ion production.

02:40 That is done via protein digestion through feedback in the intestines.

02:46 Okay. So let’s now talk through the precise way in which acetylcholine directly and indirectly stimulates acid release.

02:57 The direct way is using the cranial nerve number X to stimulate muscarinic receptors on the parietal cell, and that is directly done via ACh.

03:11 The second way is for ACh to stimulate ECL cells, which then cause the release of histamine, and histamine can then increase the amount of hydrogen ion production.

03:25 And the final way is that acetylcholine also stimulates G cells to release gastrin, and gastrin stimulates both the ECL cells and the parietal cells directly, and so you get even further increases in hydrogen ion production.

03:43 And I hope you’re thinking right now, “Okay, there is a lot of ways to increase hydrogen ion production.” And this is interesting because anytime there are multiple methods to do the same thing, it is even more highly regulated than a process that only uses one kind of way.

04:02 So we’re using multiple methods to stimulate the same thing, and these redundant mechanisms can sometimes be targeted pharmacologically to decrease certain types of ion production, and we’ll get into that in a few slides.

04:19 Okay. Let’s get into the nuts and bolts of this.

04:24 Acetylcholine stimulates muscarinic receptors on the parietal cell.

04:29 These are G-coupled protein receptors that increase phospholipase C, which cause a reaction to change IP3 and DAG formation.

04:40 The nice thing about IP3 is it’s going to cause calcium release from the endoplasmic reticulum.

04:46 DAG causes protein phosphorylation of a specially protein kinase C Both calcium and protein kinase C will stimulate the hydrogen ion pump.

04:58 Now, that’s mechanism number one.

05:01 The next mechanism is gastrin.

05:04 Gastrin works through cholecystokinin receptors, and also stimulates or activates phospholipase C, and therefore, releases calcium and phosphorolyzes protein kinase C to increase hydrogen ion production.

05:21 So both acetylcholine and gastrin work through the same mechanism.

05:26 Histamine, which is also a stimulator of hydrogen ion production, works through an alternate mechanism.

05:31 It works through histamine 2 receptors that are -- that stimulate another G-coupled protein receptor, that stimulates G-alpha S and adenylate cyclase.

05:41 This increases the amount of cyclic AMP and phosphorylization of protein kinase A, which then stimulates the hydrogen ion pump.

05:51 You may ask, “Well, here’s two different pathways acting potentially at the same time, why is that important?” Well, interestingly, they can potentiate each other.

06:01 Meaning that if you stimulate both pathways at the same time, you get more acid production than if you would have stimulated one or the other by themselves.

06:11 So this kind of synergistic release or combining of pathways allow for even more acid production.

06:18 So now that we went through our three big acid producers, there has to be something that shuts this system off.

06:24 Well, remember, from D cells, somatostatin is released, and that works through somatostatin receptors, and that shuts off adenylate cyclase.

06:33 So there’s less phosphorylation of protein kinase A, and therefore, less hydrogen ion pumping.

06:41 The last mechanism that kind of shut things down are prostaglandins.

06:45 Prostaglandins can also work through adenylate cyclase to decrease the amount of cyclic AMP and protein kinase A, and therefore, decrease the overall ability to engage the hydrogen ion pump.

07:01 Now, why is this important pharmacologically for disorders that have too much acid production in the stomach? Well, it’s a nice thing because you can target certain aspects of this system.

07:14 Maybe you want to target just one of the pathways, such as targeting the histamine pathway.

07:21 If you block that histamine pathway, you will still get some acid production from acetylcholine, but you won’t get the potentiation of acid production.

07:30 So that’s one way you can have someone who has too much acid production to decrease it a little bit but not shut it off totally.

07:39 Another way you could target this system is giving a proton pump inhibitor type of a drug, and that could decrease the amount of hydrogen ion pumping into the stomach, and that’s another way that you can kind of temper this particular system.