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BIO270 Lecture 2.doc

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University of Toronto St. George
David Lovejoy

Wednesday, October 28, 2009 BIO270 Lecture 2 - There was a rather Gaussian bell-curve with the test marks so they can’t inflate the marks. - People usually do quite well in his section. He puts a focus on slightly different aspects than what Dr. Forder did & some of the questions he’s had from various students were the large numbers of details & particularly some of the chemistry, there was a lot of chemistry in that material. Well, endocrinology is really all chemistry so he’s going to be spending a fair amount of time discussing those basic concepts. You’ll find, he thinks, what you learn in his class will help you with the material from the 1 part. - Also 20% of the mark is based on the labs & people generally do quite well on the labs so for those who are concerned about the mark, he would say that statistically the mark will go up. However, if you have concerns about it, don’t be afraid to go see him about it & if you have the opportunity to go to the help hours, the office hours, do go. - **The final isn’t just going to be his questions – one of the problems is that we have to have equal percentage so there’s going to be roughly 40% of his materist, 40% of Dr. Forder’s material & then 20% labs. There will be SOME questions from the 1 section on the final but we haven’t figured out how many yet. What we will do will be very fair.** He wants us to do well in the course. - Amine-based hormones, it’s another class of hormones & these are hormones that are based on amino acids. - What’s an amino acid? Amino acids have an amine end. - NH 2s an amino group – you’ll note that it plays a role with bases & alkalis such like this. - These amino acids are very interesting b/c in some ways they act like a base & in some ways, they act like an acid & then they have a number of very interesting properties & if you ever had a opportunity to read some of these studies that went back & tried to understand how life evolved & looked at the development of the 1 biogenic molecules that occurred before life evolved, amines, glycine, serine, glutamic acid, these were things that could be synthesized just with what was considered to be the primitive atmosphere at the time & some energy source like lightning or heat, something along those lines. So they’ve had a very long history, these amine molecules, & b/c of that, they’ve been exploited in biological systems to do a variety of things & as a result there are a huge number of these amine based hormones. - Serotonin: which is also called 5-HT. He’ll tell us about the drug afterwards. - Melatonin: closely related to serotonin, part of the same synthetic pathway – this is the stuff that makes you go to sleep. - Thyroid hormones: which are a bit more derived. - Biogenic amines: they have life-giving properties. - True hormones: a hormone is something that is actually secreted into the circulatory system & it moves around. But a number are neurotransmitters which are associated with the transmission of one nerve impulse from one neuron to another, but some are both, a number of them actually. - Hydrophilic: they are very aqueous, they will prefer water & act in that way. Of course, there are always exceptions, there is no rule that does not have an exception. The thyroid hormones are very hydrophobic b/c they, in some ways, are more like steroids & how they act. - And they have a huge gallant of effects. Acetylcholine is the hormone associated with muscle movement; serotonin is the stuff that gets you all excited & helps with your dreaming & if you’ve done LSD, it’s the stuff that gives you hives. - Some of the amino acid hormones that we’re going to be talking about are listed in the slide. - GABA acts as a neurotransmitter; glutamic acid acts as a neurotransmitter to a certain degree & recently, a number of these things have also been discovered, that they also play a role in signaling. We’re not entirely sure what they do, but they seem to & there’s probably others – there’s some evidence that, lycine for example, also does that. So these are just a couple of examples but there are probably more. - Now b/c these are hydrophilic, they like water, obviously they are lipo-phobic so lipid-insoluble hormones, that means they cannot cross the plasma membrane. - So it’s like some of the other systems that we’ve talked about. Our ligand comes, it binds to the plasma membrane receptor & it causes a signal transduction cascade & there’s a number of different systems that will work, we’ll talk about some of them in this course, & what it will do is turn on a secondary messenger system - So here’s our primary effector & now we have a secondary effector that occurs through an enzyme action associated with the receptor & then that will bind to a number of what are called effector proteins, all kinds of them, phosphatases, kinases, there can be probably hundreds, & then it’d produce usually a series of transient effects so these will be effects that will tell the cell to do something – i.e. contract or squirted juice. - The thyroid hormones are a bit different. - This is tyrosine, which is an amino acid. You don’t have to know these structures, but what you should know is that tyrosine does have this phenyl ring here which is very hydrophobic – see the double bonds here, it’s the same as benzene ring, phenyl ring, you’ll note that that structure is also an ester-diol as well, but it’s very hydrophobic & this is what tyrosine is & a couple of tyrosines then come together & they get iodinated so an iodine gets added to these things, to the phenyl rings, so one reason that the iodide salt is b/c we don’t get a large amount of iodine in our diet so they put it in salt so we have sufficient iodine – if the iodine is not present in nutrition, then there is a lack of functional hormone here so we do need that iodine & mostly the iodine is Tyrosine  Monoiodotyrosine & concentrated in our thyroid glands b/c that’s where all the Diiodotyrosine  Triiodothyronine (T )  3 reaction takes place & then what happens is that this reaction Tetraiodothyronine (Thyroxine, T ) 4 comes together, this region gets cleaved & it becomes attached to this other tyrosine molecule & then we have the 1 of 2 hormones called triiodothyronine or T & that has 3 iodines – if there are 3 four, then it is referred to as tetraiodothyronine & 4 . - These are very typical clinical tests, if you have thyroid issues, if there’s an issue with your thyroid gland, typically what they’ll do is they’ll monitor the concentrations of T & T i3 your 4 bloodstream, they’re very useful diagnostic parameters for this. - Thyroid hormones are very hydrophobic – as I mentioned they kind of act as steroid hormones. In fact, the hormones or the receptors for thyroid hormones are very similar to the steroid hormones or steroid receptors & they’re considered part of a super class, so we think of the thyroid-steroid receptor super class in that the nuclei receptors are like added transcription factors. - Unlike the steroids, where we mentioned that some steroids do have a plasma membrane receptor, these do not very interestingly, but they’re very hydrophobic, they have a carrier protein as well, the same way that steroids have a protein, globulins & such, passes right through the membrane & it can bind to either a receptor here in the cytosol or a receptor in the nucleus. If it binds to the cytosol, it gets translocated, then the complex binds directly to DNA & it acts to turn genes on, genes off. - Thyroid hormones play a very major role in development, in differentiation b/c of its effect directly on the genome, on genes, but they don’t have the same effects that you might expect with amines – with amines, it’s a very fast reaction, transient effect. Thyroid hormones act more like steroids so when we start looking at how these hormones start to interact, we’ll just touch on it this year, you’ll see that their reactions, their actions are much slower & they have more of a modulatory effect. - So all of these are part of one synthetic pathway. No, I’m not going to give you that whole pathway. Dopamine at some point gets converted into epinephrine which then gets converted to norepinephrine. - Dopamine is a neural hormone, it’s associated with things like reward, with locomotion – Parkinson’s disease for example is a problem where there’s not enough dopamine that’s produced & so your brain cannot coordinate a number of the locomotor actions & so we start to shake. - Epinephrine or adrenaline, this is the stuff that’s associated with stress & energy production. You’re walking to school one day & suddenly a lion leaps out from behind a garbage can & you get that etch in your stomach – that’s adrenaline being released, it’s epinephrine being released from your adrenal gland, it’s very fast reaction from your brain there & this is part of the fight or flight response & this prepares you that you’re about to come across a major challenge. - Norepinephrine which is released from terminals in the peripheral nervous system, but it’s also part of the brain. Epinephrine, very interestingly, is not in the brain, you can find dopamine & norepinephrine is used in the brain but not epinephrine. Norepinephrine is associated with a different stress so if you’re visiting your uncle’s farm & he says ‘alright, we’ve got to put in 137 fence posts today’, that work that keeps you going, that’s what norepinephrine does. This is work related stress, this is emotional related stress, these hormones & they’re coming & going all day long. - They’re called catecholamines b/c they have a catechol group – a catechol group is this benzene ring here with the 2 hydroxyl groups so anything with this group usually has the word catechol in it. Again you don’t need to know the structures, but you should know the catecholamines, these 3 have this catechol group. - The adrenal medulla, even though it’s down there, it’s actually part of the nervous system. The adrenal gland, which we’ll talk about in a bit more details later, is a different part & different animals have different structures for all of the adrenal gland comes together, but the medulla, the part inside the adrenal gland, is actually all nervous tissue & it’s part of the peripheral nervous system. Each adrenal gland is separated into 2 distinct structures, the adrenal cortex & medulla, both of which produce hormones. The cortex mainly produces cortisol, aldosterone, & androgens, while the medulla chiefly produces epinephrine & norepinephrine. - Catecholamines follows the same way as amines – here’s your clue, if it’s got amine in there, it’s probably fairly hydrophilic & it works same way as other amine molecules so it binds the plasma membrane receptor, stimulates a secondary messenger, cascade & then turns on a number of protein systems & then has a number of transient effects in the cells. - Again, I just put this here to help orient where you are, but you don’t need to know these structures. - They’re called this b/c they’re derived from tryptophan which is an amino acid – now your body cannot synthesize tryptophan & tryptophan is one of those few amino acids you have to get entirely from your diet & through a couple of different reactions, we end up with serotonin. **Don’t worry about the structure – all you have to do is refer to this as monoamine.** Serotonin is very interesting b/c it’s present in virtually all life forms, it’s all through the animal kingdom & plant kingdom, fungi – this suggests that this as a hormone, evolved probably 2 or 3 billion years ago. - Serotonin, if the appropriate enzymes are present, will produce melatonin – this is the hormone that is associated with sleeping – when you sleep, this hormone starts to rise & even if you take melatonin, it will make you drowsy to a certain degree. Now you can buy this stuff over the counter & people were taking grand quantities of this at some point to overcome jet lag & some people who worked with shift work had some difficulty as well. You can buy melatonin on the counters – some people say it works, others say it doesn’t work but melatonin is a very small molecule, as is 5-HT here, or serotonin, if you take grand quantities of this, you’re going to have a certain amount of that that will either be converted to serotonin through reverse reactions or it will simply bind to the serotonin receptor & cause serotonin actions – some of the dreaming that’s associated & some of that great vivid dreams, but serotonin has been implicated with a lot of hallucinogenic actions of some of these drugs & with dreaming as well. It also plays a very major role in the regulation of virtually everything in your brain. - Eicosanoids are based on the fatty acids in the phospholipids of the membrane – all you need to know is it’s fatty acid derived. They have all kinds of structures, but it’s a fatty acid & you know how fatty acids are like – they’re very hydrophobic. - They’re paracrines – they’re produced, they immediately leave the cell & get picked up by the surrounding cells. - Cannabinoids: a number of years ago, there was a group at the National Institute of Health & they had come up with a new receptor & they thought they were looking for a vasopressin receptor & they started looking for it, they tried vasopressin, but vasopressin didn’t bind & they tried oxytocin b/c it’s like vasopressin, it didn’t bind so they were really desperate & they got to the point where they were trying every single hormone that they could come across & nothing would bind to this bloody receptor & the grad student who was working on it was getting really depressed b/c it wasn’t going very well b/c she had to find something to turn this receptor system on so one time, she was together with another grad student & told the grad student ‘well our laboratory is looking on the neurological effects of cannabis, but we’ve got this receptor & nothing binds to it’ & the grad student was like ‘hey I’ve got this wacky idea, why don’t we see, just for laughs, if tetrahydrocannabinol, the active ingredient in marijuana, let’s see if it binds to your receptor’ so they tried it & it bound & that’s how they found the cannabinoid receptor. - So once they knew this, this was really exciting – okay, that’s why you get high from this stuff – no one knew how marijuana worked up until that point – they thought that it was mimicking steroids & it was working on some of the steroid receptors, but now they had a distinct receptor in the brain & saw that it was binding THC, but if it binds THC, that must mean there’s a hormone in the brain that binds to this receptor – that’s how these things work so they did the search & they came up with these cannabinoids & when they found it, they found that it was related to the eicosanoids & these things play a role with reward & emotionality, stress – very interesting set of hormones. - If we go to eicosanoids in general, they’re produced by most tissues & generally act as paracrine signaling agents. - Taking too much aspirin can be a little problematic b/c it can inhibit that synthetic pathway that’s occurring virtually in every single cell in the body so it’s very profound drug. - Well, I think pretty much, they all have to act as paracrine agents – one of the problems with the gases & we’re talking about a couple of small gases, NO, CO & then hydrogen sulfide has been added to the list – these are very small molecules – the trouble is once they’re produced, they can’t go very far before they bind to something so they have a very short span of action. - We’re not talking about these, but I just wanted to give you a sense that these ones do exist. - Here’s just a cartoon of this. - They diffuse readily through the membrane & they will act on intracellular receptors & can produce a number of effects. - Sometimes they can be produced right within the cell & then they act locally within the cell so very short lived & have very local effects. - Purines: AMP: adenosine monophosphate; ATP: adenosine triphosphate; GTP: guanosine triphosphate. - Again we’re not going to spend too much time talking about those. - Isoprenoids: (read slide) – if you decide to go into insect endocrinology, which is quite interesting, this is the major hormone type that you’ll be working – insects don’t readily produce steroids & it’s been thought that these isoprenoids take over some of their functions. - Inorganic ions: Ca & Mg, which I alluded to in the last class, can still be classified as a messenger system. - Ca & Mg can bind to the plasma membrane receptors, or channels, or intracellular receptors. - There’s a number of different channels that other hormones will act to operate to allow this for passing through into the cell. - It’s noted that these are probably the earliest & oldest hormone type systems, well signaling systems, can’t really call them a hormone & it’s been thought that they evolved with the earliest cells 4 billion years ago. - Now that you know who the players are, now we can talk about who they are binding to. Now there are some basic concepts that are important with receptor-ligand interactions & back in the olden days, we called this thermodynamics or pharmacokinetics – now we call it receptor-ligand interactions & we’re not going into the thermodynamic equations. - Student Question: What do you have to learn for the test? He’s going to be covering a fair amount of material in his lectures & there’s a certain amount of material that’s not in our book & then there’s a certain amount of material that’s in the book that’s not covered in his lectures – he’s not going to ask us to learn details in the book if he hasn’t talked about them – only responsible for the details that he talks about. When you are looking at those readings, it will cover the same material that he’s covering – they will approach it by a slightly different angle & that will help you but only the parts that intersect will be tested on. - Receptors on target cell: There are a few exceptions – the eicosanoids, the cannabinoids, are hydrophobic, but they bind to plasma membrane receptors. - The basic concept is that the receptor changes shape when the ligand binds – that is the simplest, the reality is there is electron flows & proton flows & everything that occurs, all kinds of energy gradients that happen, but you don’t need to know that. - There are actually all kinds of examples that are not natural that bind to the receptor. What is a natural ligand? If you go to the drug store or health food shop, you can take all of these natural supplements – there are a number of supplements out there that you can take to enhance various parts of your anatomy, these are natural ways of enhancing your anatomy, but they are not the hormones that are found in your body – if they’re not found in your body, is that natural? So there’s a whole variety of things that these plants have produced, phytoestrogens, that you can use to enhance things & these things come from legumes, soy, peas, beans, these sort of things & it mimics the estradiol receptor, but it’s not naturally found in your body & is this a natural supplement – your body doesn’t break it down normally – it treats it like a foreign molecule, but it does bind to the estradiol receptor & it is naturally produced in that there’s a plant out there that produces it. Now the reason that plant produces it is b/c it acts as a contraceptive – you’ve got all these cows wanting to eat all of the clovers & the clovers aren’t really impressed by this so they produce all of these phytoestrogens so it acts as a contraceptive to grazing species – cattle can’t produce or the animals can’t produce & so it cuts down the grazing pressure – that’s why these things exist. Now is that natural, I’ll leave it up to you. In my opinion, this is not natural b/c it’s not part of the normal endocrine cascade. - There are 2 classes: agonists which will activate the receptors – something that will simply binds to the same receptor & produce a response; if it blocks the receptor on the other hand, it’s called an antagonist. - All drugs that you take are receptor agonists or antagonists, anything that acts on your endocrine system, whether you get it over the counter or whether you go & start eating a chunk of clover, they can all be classified as agonists or antagonists. - Here’s just a schematic of that. - Here’s our ligand & it binds to the receptor & you get a response. A non-ligand, something that’s totally unrelated, it’s not recognized by the receptor to any great degree & there’s no response so it’s just not a ligand. - On the other hand, with an agonist, it does the same thing as the natural ligand in that it will bind to the receptor & cause a response but almost always, the agonist, in almost all situations, will never ever have the same effect as the natural ligand – it will be different in a number of ways. - The antagonist on the other hand blocks the receptor & so you get no response. - Why is this different from that? An antagonist will stop the receptor from being activated – the big difference b/w an agonist & an antagonist as opposed to a non-ligand is that these have a certain affinity for the receptor, they have a certain match – one of the things to think about is when a ligand binds a receptor, it’s not a matter of it binding & stays bound, it doesn’t do that – what these things do is they bind, they let go, they bind, they let go, this happens all the time, thousands of times every second – if a ligand has a high affinity for the receptor, it will bind & it will hang out there a little bit longer so it will bind & let go for longer, bind & sometimes, maybe it will get internalized. - A low affinity receptor will bind & let go immediately, that means that if something has high affinity & it hangs out bound to the receptor for a longer period of time, that increases the probability that that receptor will be activated. One that has low affinity, it’s not going to bind for very long & so, it’s going to decrease the probability so using the example of phytoestrogens from clovers or soy, they have very low affinity, they have 1/1000th the affinity for the estradiol receptor as what estradiol does so it binds & produces only a small effect. - If on the other hand, you increase the concentration of these ligands, then again you can increase the probability these receptors will be occupied. - So those are the concepts you need to think about – we’ll talk a little bit about those. - Genes occur in families as you know. Way back when, a few billion years ago, there were a few genes & then as organisms evolved & genes evolved, genes would duplicate, entire genomes would become duplicated so if you have one gene initially & the whole system duplicates, you now have 2 genes. If one of those genes is a receptor, now you have 2 receptors, but over time, they get selected for slightly different functions & so, the receptor structure changes a little bit. Now the same thing happens to the ligands – the ligands may change b/c the enzymes that synthesize them change & produces a slightly different variant of the ligand or in the case of peptides, proteins, then the entire gene changes so you have these families. - So for example, dopamine, epinephrine, norepinephrine, they bind to very similar receptors. 5-HT, serotonin & melatonin also bind to similar receptors. Growth hormone & prolactin bind to similar receptors – they have a family together. - Expressed on different target cells: so they don’t necessarily all be expressed on the same place & you can get different responses to the same ligand so what you can get, let’s just consider 2 different ligands, 2 different receptors that occurred through a gene duplication so we have receptor A – well both ligand A & ligand B can bind to receptor A, but ligand A would have perhaps higher affinity for receptor A than ligand B would & by the same token, receptor B might have higher affinity for ligand B, less affinity for ligand A. When ligand A binds to receptor B
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