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
- Serotonin: which is also called 5-HT. He’ll tell us about the
- 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
- 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
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
- 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
- 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
- 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
- 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
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
- 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
- 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
- Purines: AMP: adenosine monophosphate; ATP: adenosine
triphosphate; GTP: guanosine triphosphate.
- Again we’re not going to spend too much time talking about
- 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
- 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