all right so the end of our last section we started looking at how cyclic amp can serve as a second messenger system for some hydrophilic hormones and again for hydrophilic hormones you want to sort of ask yourself what you know about those as you kind of go along to help you review and kind of drive this message home so for hydrophilic hormones we are dealing primarily with hormones that are based on either one or two amino acids or sometimes longer chains of amino acids because they're hydrophilic of course we know they don't need health traveling in the blood because the blood is mostly plasma it's mostly water and so hydrophilic hormones therefore are pretty heavy traveling in the blood and because they're hydrophilic again they're not able to cross the plasma membrane of the target cells instead they bind to extracellular receptors on the plasma membrane of those target cells and because they're binding on the outside of the cells of course we have to have a second messenger system at least if not a third order messenger system as well to trigger that change in gene expression inside that target cell all right so that's a little bit of review from the previous section i know i went through that kind of fast but of course you can go back and listen to it again if you need to but what we're going to move on to now is a section that talks about another way of achieving that second messenger system involving hydrophilic hormones that's just a little bit more complicated but big picture is really very close to the same thing as a cyclic amp system the details are different but the overall big picture is the same we've got a hormone on the outside of the cell can't get in membranes hydrophobic right so the hydrophilic hormone can't get in so it needs a second messenger system or a middleman in order to trigger that change in gene expression inside the cell and actually receive a or achieve a response of that target cell to whatever needs to happen so our second messenger system is going to start off very similar to our other second messenger system we talked about the homocyclic amp we have the hormone binding to receptor on the outside of the cell and activation of a g protein just like we saw with the cyclic amp system but now we're not going to be looking at a second messenger system involving cyclic amp we're actually looking at calcium ions so whenever you see ca2 plus this is calcium ion we have a calcium ion system that's going to involve not adenylate cyclase to produce cyclic amp but instead a type of what's called phospholipase all right so we'll see more about phospholipase here in a second but specifically what we're going to be looking at here is a bigger chemical called phosphatidylinositol 4 5-bisphosphate that's a mouthful uh phosphatidylenostol 4-5 bisphosphate or just plp2 for short totally fine to say plp2 this is actually kind of like two second messengers locked together and inactivated but if you break plp2 into its components you actually get your second messengers which can then achieve that change of gene expression that we're looking for in the target cell all right so what i want you to do is picture plp2 is a larger molecule that has not yet been cut all right we've got this big thing it's inactivated and can only become activated when it's cut into its two smaller sub-component pieces so as it says it's a storage form for two second messengers we haven't talked about who they are yet but we're about to but it's only when this plp ii is cut that these two second messengers show up and become active all right so the steps involved here again overall big picture not that different from the cyclic amp system but the details again are what is a little bit more uh involved so the first thing is to happen is the agonist which in this case is the hydrophilic hormone is going to bond to the receptor outside the cell in that plasma membrane so again we're dealing with an extracellular receptor now once that hormone binds to the extracellular receptor there is going to be um the activation essentially of a g protein to bind to gtp just like we saw back when we were triggering internally cyclase to produce cyclic amp so again first step really really similar to the other second messenger system we saw but now instead of activating an l-a cyclase we're going to actually eventually activate that phospholipase c all right so phospholipase c uh i want you to picture a plc here phospholipid as the scissors that are going to cut this bigger molecule in two thereby activating its two subcomponents which can then actually go ahead and be second messengers all right so phospholipase c is an enzyme we know that because it ends in ace right we always know that enzymes end in ace so phospholipase c is going to be the scissors that cuts phosphatidylenostol 4-5-phosphate or plp-2 into its two smaller sub-component pieces so once we've activated phospholipase c that is going to cut plp2 again this big name up here the phospholipase c cuts the phosphatidylenostol45 bisphosphate into the two subcomponent pieces of dieselglycerol and an ostoltrous phosphate now again i'm totally cool with you guys just knowing the acronyms here okay if you know plc plp2 dag and ip3 and how they kind of all fit together i'm good i'm thrilled if you know that much you don't have to know the actual spelled out names of these things because they're they're fairly challenging i mean they're hard to say and they're hard to spell so if you know the acronyms i'm happy all right so what i want you to go back maybe draw a flow chart right you've got activation of plc which cuts plp two into dag and ip3 all right so it's like a imagine drawing this out as an arrow where you've got pop2 you've got an arrow and above the arrow is plc because the enzyme is what actually catalyzes this reaction pop2 is actually cut down then on the other side of the arrow you're going to have dag and ip3 and those guys are your second messengers which are going to actually trigger the change in gene expression inside the cell now sometimes you're going to actually have a third order messenger as well as we're going to see in a second but the basics of this really involve going through dag and ip3 as the second messengers all right so again think about parallels here comparing this to the cyclic amp system that cutting of plp too into dag and ip3 is effectively functionally the same thing as the formation of cyclic amp was in our other second messengers than we talked about at the end of our previous section okay again details are different but the overall big picture is the same we're trying to activate second messengers which can actually achieve our change in gene expression all right so as far as specifically what ip3 and dag do the inositol tris phosphate again that's your ip3 is going to trigger a release of calcium ions from inside the cell now what part of a cell stores calcium ions all right that's a question back from your general biology your fundamentals of biology biology 1200 in in in lakewood's case possibly algae 1510 but it's a basic cell biology question calcium ions are stored in the cycle i'm sorry in the smooth endoplasmic reticulum in this case inside of the cell so the smooth er is storing calcium ions that is thing that are then going to be released as ip3 is produced from that plp2 precursor all right so that's one aspect of this the other aspect of this is that calcium ions can act as a third order messenger in uh involved in producing that change in gene expression that we're looking for all right so we've got our ip3 triggering calcium ion release we've got dieselglycerol or dig certainly serving as a second messenger directly and those calcium ions which were released from the smoothie are as a result of ip3 being present are then going to possibly become a third-order messenger depending on which kind of hormone we're dealing with specifically all right now if we think about calcium ions inside of cells they actually show up a lot of places right we can think about calcium ions being used in the release of neurotransmitters all right we can think about calcium ions being released in terms of inducing um muscle contraction right so it's it's a pretty um it's a kind of ubiquitous ion used inside of cells for signaling lots of things but in this case the calcium ions are being used to trigger that change in gene expression which is what's needed after a hormone has been received by a target cell we also have dieselglycerol functionally creating the potential for protein kinase c to be activated within the plasma membrane this could also be a second messenger to either activate or deactivate a target cell based again depending on which hormone we're dealing with so we have some other kind of maybe smaller details we can think about here as well protein kinase c has to have calcium ions present in order to be activated and therefore change how that target cell is behaving um we also have uh protein kinase c can phosphorylate serine and threonine okay so there's kind of a lot to that story as well serine and threonine are both amino acids and when an enzyme phosphorylates another molecule what that does typically is either activate or deactivate it depending on what kind of molecule we're dealing with so in this case we're actually going to create target proteins from serine and threonine due to the phosphorylation action of protein kinase c all right so we can kind of add a little bit more to the story here when we're dealing with what these different components of the cells are doing once that hormone has shown up but this is actually a pretty good look at what's going on with this second messenger system right so we've got our water soluble hormone it hooks up with that g protein link receptor on the outside of the plasma membrane that's then going to activate phospholipase c right so phospholipid remembers our scissors or in this case apparently a hatchet we're going to take our phospholipase c and use that to cut the um plp2 into an osteltrous phosphate and diazoglycerol okay so ip3 then can actually trigger an activation of protein kinase c diisoglycerol can do the same thing albeit in different ways ip3 does it by causing an influx of calcium ions to then cause activation of protein kinase c which again can then be used to uh to change siri and threading into other kinds of things whereas dioglycerol can just activate protein kinase directly all right so in this case we have um calcium ions here as a third order messenger not always have it doesn't always have to be the case or it doesn't always have to work that way but in this case it is to achieve that second order messenger system and eventually change the gene expression and again i've linked you here to another youtube video which i think is pretty good to help explain this um but i can say from personal experience i i personally think the best way is to take what i've been saying to you and try to draw it out on a piece of paper with a flow chart kind of like this but sort of make your own and and use that to kind of get this cemented into your brain because this is this is a little bit complicated um it's not maybe enough just to hear it and then move on and sort of figure that you understand it completely you kind of have to take it and sort of make it your own right make it into a form that you create using your brain that's going to help us thinking better to um to what you're trying to learn here and we're going to find a lot of things like that in physiology kind of on a tangent here for a second uh because it's early in the course right a lot of times after a few weeks people start asking me well how would you recommend studying and i always always always say find a way to make it your own don't just take my word for it don't just listen to what i'm saying take it and draw a flow chart or write out some notes and then explain that out loud to somebody do something to make it your own and by processing it in your brain that way it becomes part of you and you will remember it much better than if you just try to memorize it and and spit it back to me in the same form that i um i presented it in uh so again the basic idea here uh where we are is we are dealing with hydrophilic hormones achieving effects in their target cells now in some cases we might use cyclic amp but in other cases we might use this other situation where we have our phospholipase c rplp2 iv3 dag also calcium ions protein kinase c the details are different but the big picture is the same it's cyclic amp it's it's really a parallel system that does basically the same thing all right so a couple of other things here dealing with hydrophilic hormones before we move on to the lipophilic hormones um we also have a few other situations here amines are molecules made from amino acids but they're not linked together by peptide bonds right so they're not uh it's not that we have amino acids linked together to make proteins it's so we have amino acids that have been processed into other kinds of smaller molecules which then act essentially as a hormone so in this case um the amines for example can be used to target the autonomic nervous system right so we can have a means that are involved in activating the sympathetic we can have a means that involve activating the parasympathetic and vice versa right so the the the nervous system also results in the release of these amines as well um so things like acetylcholine right acetylcholine is a neurotransmitter that affects both the sympathetic and the parasympathetic nervous system in different ways if you have acetylcholine release in some areas of the body that's going to be more of a fight-or-flight response but in other contexts in other areas of the body it can actually serve a parasympathetic function so acetylcholine is actually a really important one the sympathetic nervous system uh getting fight or flight right parasympathetic nervous system is more of a rest and digest type system um in other cases rather than using using these as neurotransmitters there are cases when the cells releasing acetylcholine for example might just release it straight into the blood or might release epinephrine and norepinephrine straight into the blood in that case it's going to be a different effect right the norepinephrine is involved in fight or flight right but as far as the effect that it has it depends on whether it's used in sort of a cell by cell basis or whether it's cells releasing norepinephrine directly into the blood so let's talk about that for a second if we have essentially adrenaline being released into nerve fibers or around nerve fibers that's going to be a little bit of a tiny fight or flight type situation so if somebody uh jumps out from behind the door and yells boo right that's gonna be a really like short lived temporary sort of uh fight or flight kind of a thing like you're startled for a second but then it's it's done right it's a relatively short term thing it's not like you're feeling the effects of that five minutes from now in that case because in that case the epinephrine hasn't actually gone into the blood it's not affecting other areas of the body and you don't have to work it out of your blood for the effect to be over it's simply a matter of epinephrine affecting specific nerve fibers and then just being done now on the other hand if you have a really really big scare like if you um are in a situation where you have just narrowly avoided being in a really bad car accident you pull off to the side of the road and you sort of like your cold sweat and you're shaking and you know it's that kind of response does not feel good at all that is more of um epinephrine going into the bloodstream so in that case uh you still get the fight or flight but it's a much more powerful thing because it's throughout your entire body the blood is transporting adrenaline everywhere in your body and you're going to feel effects throughout your entire body you're going to have a dry mouth you're going to have the sweating you're going to have dilation of pupils you're going to have all kinds of things working in that case i guess constriction pupils you have all kinds of things happening throughout your entire body and it takes a couple of minutes for those effects to go away it's not like the the small scare where you were startled and then you were fine in this case it's going to take a few minutes to kind of run its course because the adrenaline has to be kind of processed out of your blood again for this the scare effect to go away so much longer in that case now what about this what about uh what about if you need to take something like epinephrine in terms of um uh reversing like a situation like anaphylactic shock right so why say say for example somebody is is stung by a bee and they are allergic to bee stings they know they need to get some adrenaline into their system quickly otherwise they're gonna have some potentially very dangerous effects um why don't they just have like an epinephrine pill that they could take to make them kind of reverse the effects of that bee sting and the potential shock that might be coming up shortly thereafter um well a really good reason for that right so um epinephrine and norepinephrine if you were to take them orally because they are hydrophilic and because they are essentially like protein based they would be digested in the stomach before they ever had a chance to be absorbed into the blood and so you could take your epinephrine pill but it would get broken down before it ever had a chance to do anything right now on the other hand if you inject adrenaline or epinephrine um directly into the blood you bypass the stomach you bypass the uh the potential for digestion and in that case you actually get the the um sorry you achieve the effect that you're looking for with the epinephrine in that case uh reversing the potential from anaphylactic shock because the bee sting so it's important to think about you know why we have to take some of the medicines we do whether it's orally whether it's intravenously or other there's a really good reason for it it's because if you take it the wrong way it may not work in this case because the the medicine won't actually be digested before it ever has a chance to operate now again kind of a side note here but sometimes these things are kind of interesting if you think about asthma inhalers asthma inhaler's been around for decades and essentially what they contain is albuterol typically which is a it's a an alternate form of epinephrine we'll say it that way so it's not epinephrine but it's a derivative of epinephrine so it still has some of the same effects but it's not as powerful and it's not as systemically disruptive as taking adrenaline would be directly as it's like inhaling it right so just to give you an idea of kind of how things progress in medicine back in the old days back before we had albuterol asthma inhalers they actually used epinephrine inhalers all right so you could actually take an and a sort of almost like atomized form of epinephrine breathe it in to reverse the effects of an asthma attack because what an asthma attack is at its root is a constriction of muscles in your bronchial tree all right so you want to get those muscles to relax to open things back up and to allow more relaxed breathing that's a basic idea now back in the old days before albuterol was around they would actually give people asthma inhalers that had straight up epinephrine in them which is is going to work it's going to open up that bronchial tree but it's also going to have a whole lot of other intent i'm sorry unintended side effects by simply breathing adrenaline um you're you're going to have some um not long lasting but some fairly short-lived intense effects almost like an adrenaline rush by hitting that asthma inhaler during an asthma attack so now albuterol is a much less disruptive kind of a medicine and it's it's uh much easier to use for that reason all right so just kind of wrapping up our hydrophilic hormones um we're looking at things like calcitonin we're looking at most of the pituitary hormones we're looking at the parathyroid hormone the pancreatic hormones insulin and glucagon all of these are hydrophilic hormones all these are water-soluble hormones all of these must find target cells that have receptors on their plasma membrane because they cannot get into the cells reason being the cell's plasma membrane is hydrophobic and these hydrophilic hormones simply can't cross a hydrophobic barrier so what happens when the hormones hit the receptors on the outside of the cell is that we need to have some sort of secondary or secondary and tertiary messenger to actually trigger the cell to respond appropriately to whatever that hormone is trying to accomplish right the basic idea here is to change gene expression to change how things are being transcribed and translated either to create more proteins or create fewer proteins again the specifics depend on the protein and the warm one in question but that's the basic idea here the second third order messengers chains also can sometimes amplify the effect so in some in basically what we mean by that is that a single molecule of hormone can actually result in the formation of many molecules for example of cyclic amp so it's not a one-to-one sort of translation here where you've got you know one molecule of hormone gives you one dental cyclase which gives you one cyclic amp instead to make it more efficient you need one molecule of hormone to activate one adenylic cyclase enzyme molecule and that will then create maybe dozens or hundreds of molecules of cyclic amp which then have the effect of altering gene expression we talked about phosphoryl relation to proteins and we talked about why these have to be intravenous because if you take any of or if you were to take or consume any of these hormones by swallowing them they would essentially be digested in the stomach now not that you're typically going to take um i don't know calcitonin in a pill but we can think about insulin right so insulin shots which are taken by type 1 diabetic patients we'll talk about that later on in this chapter you have to inject it because if you were to consume insulin orally it would be digested in the stomach before it even has a chance to be absorbed by the small intestine so there's a really good reason why these medicines are taken the way they they are taken all right so with that we're going to wrap up this section um should be i think section four in the endergon chapter and we start section five we'll be dealing with lipophilic hormones uh which are much more straightforward and then from there we'll actually be getting into some specific hormones where they come from and what they do