© 2010
  University of Idaho
  All rights reserved.
  Psychology Dept.
  University of Idaho
  Design - P&D  CTI

Let’s review a little bit before we get into the neurotransmitters.  First of all again, remember that synapses have three major structures; they have presynaptic elements, postsynaptic elements and the synaptic cleft.  Again the presynaptic elements were at the end of the axon and contained a variety of different structures.  Also, as we see in slide four, the postsynaptic elements could be part of an axon, a dendrite, or a soma; and it contains a variety of structures as well.  Finally we have a space between the pre and postsynaptic elements (the synaptic cleft).  Again, as we can see on slide five, it’s about 20 to 30 nanometers wide, and contains enzymes from glia cells and postsynaptic elements that ultimately break down neurotransmitters. It also has neurofilaments that keep pre and postsynaptic elements in close proximity.

So, now what we’ve done is talk about a variety of different structures.  Now let’s begin by talking about the concepts of what is called the neurotransmitter release.  We talked about an action potential coming down and causing sodium gates and potassium gates to open.  Well, when that action potential reaches the presynaptic element, it causes voltage gated calcium channels to open.  These calcium channels go down their electrical and chemical gradients.  Ultimately, it caused the synaptic vesicles to bind with the presynaptic membrane.  When that occurs, it causes the vesicular and presynaptic membranes to combine.  Ultimately, the vesicles release the contents (called exocytosis) and they basically spewed the neurotransmitters into the synaptic cleft.  They spew this neurotransmitter in packets, and these packets are called quanta. Ultimately the release of this neurotransmitter is called quanta release. 

The neurotransmitter diffuses across the synaptic cleft and binds with the postsynaptic membrane receptors.  As a result (as we see in slide seven) we have a postsynaptic potential. Postsynaptic potentials are one of two types; they’re either excitatory postsynaptic potentials (that is they depolarize the postsynaptic element) or they’re inhibitory postsynaptic potentials (that is they hyperpolarize the element).  Postsynaptic potentials again are conducted down the neuronal membrane until they get to the hillock.  Again what we do is we summate all of these postsynaptic potentials and if we depolarize that axon hillock 15 millivolts (mv) we get an action potential, and if not we basically get nothing at all. 

When we talk about receptors there are in essence two major types.  There are ionotrophic receptors and metabotrophic receptors.  As we can see in slide nine, ionotrophic receptors are basically a receptor site with an ion channel.  In essence they are all one unit.  What we have as an example here (slide 9) is a nicotinic receptor which uses acetylcholine.  As we can see, there’s a sodium pore surrounded by a variety of different sub-units.  Ultimately acetylcholine will bind on one of these sub-units, and as a result, it will cause the pore to open and sodium enters. 

Some characteristics of ionotrophic receptors.  Well first of all they respond very, very rapidly.  We put on a little bit of neurotransmitter and the channel opens.  You take it off and the channel closes.  It’s a very simple system, and again, the ion channel is part of the receptor.  The key here is this; most of these are not as prevalent in the brain and central nervous system as the second type of receptor.

The second type of receptor (as we see in slide 11) is what we call metabotrophic receptors.  That is, they utilize some kind of metabolic process. Here, in a metabotrophic receptor, the ion channel and the receptor site is in different locations.  So what we have here is some neurotransmitter binding on the receptor binding site.  That’s gong to cause the release of some kind of messenger.  These messengers go to some kind of an ion channel, and ultimately cause that channel to open.  Ultimately these messengers inside of all these metabotrophic receptors are called intracellular messengers or second messengers [First messengers are the neurotransmitters themselves].   So, again, the ion channel and receptor sites are located in different locations and that is the difference between a metabotrophic and an ionotrophic receptor. 

So what are some characteristics of metabotrophic receptors?  Well, as we can see in slide 12, first the channel is not part of the receptor.  That is, there are a variety of different intermediate steps that must occur before the ion channel is opened.  Ultimately, what we need to do is put a phosphate group on the ion channel.  There’s a wide variety of different mechanisms in which we do that and is called phosphorlation.  Metabotrophic receptors are also slow to respond compared to ionotrophic receptors.  But, they are also slow to shut down.  That is, when you remove a neurotransmitter, you still have the system working for a while (even when the neurotransmitter is on the receptor site).  Ultimately, this provides for a lot more regulation in the system.  As a result, you can have lots of control in the system to regulate how long the ion channel stays open, under what circumstances, and a variety of other things. 

Now, there’s a wide variety of second messengers that we have out there.  Probably a couple of the most important are calcium.  Just like the calcium that we saw earlier in the presynaptic element.  There’s a wide variety, though.  So I haven’t listed them all, and it’s not important that we know them all.  But it’s important for you right now to have an understanding of some of the basic ones that are out there.  So, when we talk about guanine proteins, you have an idea about how they work. 

Now, we’ve had this neurotransmitter on the receptor site, we have this system, we have ions coming in, and you’re getting an excitatory postsynaptic potential.  Well, how do you shut down the system?  Well, as we can see in slide 14, there’s a variety of different ways.  Number one, we can remove the phosphate group that’s on the channel.  That in essence closes the ion channel and nothing comes in.  The second way to do it is to remove the second messenger.  That is you pump out the calcium or you remove some of the other second messengers that are in there.  As a result, you don’t get a phosphate group on the ion channel and the system closes and shuts down.  Finally the most basic way is we can remove the neurotransmitter.  It takes a little while before the system shuts down, but it does shut down.

So how do we remove neurotransmitter?  Well as we can see in slide 15, there’s a variety of different mechanisms.  The first way is to degrade the neurotransmitter.  That is the simplest method.  The classic example is acetlycholinesterase.  Acetlycholinesterase or AChE is basically on the surfaces of the postsynaptic membrane, and degrades acetylcholine into choline and acetate.  It’s also located in the synaptic cleft as well.  Again, there’s no major problem here, and there’s a wide variety of other substances that are out there that removes neurotransmitter.  Another classic example is mono adenine oxidase which basically breaks down norepinephrine.  We’ll talk about that at a later time.

The second way to get rid of neurotransmitter is to remove it.  The way we do that is through a process of reuptake.  That is we reabsorb the neurotransmitter that’s been released back into the presynaptic element.  Now, there’s a concept that goes along with this called the LaShachle theorem.  What it says is this.  When you have some kind of equilibrium, the neurotransmitter that’s on the receptor site is the same neurotransmitter concentration that’s not on the receptor site (not bound).  So, the amount of neurotransmitter in the synaptic cleft is the same amount of neurotransmitter that’s on the receptor.  When you remove the neurotransmitter from the cleft (that is you decrease the concentration), the neurotransmitter is pulled off the receptor.   Again, it’s based on concentration gradients that we’ve talked about earlier in this section.

So how do you degrade and bind neurotransmitters on receptor simultaneously?  Well the key here is that receptors have more affinity. As a result, the neurotransmitter will bind on the particular receptor a lot more than would bind on something else within the synaptic cleft. 

Well let’s talk about some neurotransmitters, your receptors, and how they work.  We’ll begin this on looking at slide 18.  The first of these that we want to talk about is called acetylcholine which is shown on slide 19.  Acetylcholine is the primary neurotransmitter that’s secreted in the efferent nervous system.  Basically, in the periphery, acetylcholine neurons are found in a wide variety of structures in autonomic ganglia, and primarily in the structure that we call the neuromuscular junction.  This is the neurotransmitter that’s going to be involved with muscle movement.  In the brain acetylcholine neurons are also located in a wide variety of other structures such as the Pons and the basal forebrain.  In these structures, it causes stimulatory events or stimulatory effects.

There are two different types of acetylcholine receptors and they’re classified under two groups, nicotinic receptors and muscarinic receptors.  Nicotinic receptors are found in skeletal muscle.  They basically use an ionotrophic type of system.  As you can see here, the agonist that is the cause of similar type of an effect is nicotine.  Muscarinic receptors on the other hand basically use the metabotrophic process.  They’re found in the heart and smooth muscles and other structures and they in essence use muscarine as a primary system to make it work.

On slide 21 we see the classic example of nicotinic receptor.  This is kind of a cartoon representation so we need to make sure that we understand that.  The nicotinic receptor again uses an ionotrophic model where the receptor and the ion channel are one unit.  What happens is that the acetylcholine binds to the alpha subunit.  As a result, it causes the ion pore to open.  The beta and delta sub-units are primarily concerned with regulatory functioning.  They are going to regulate how long the pore stays open, how fast it opens, etc. 

We can also put a phosphate group on these beta and delta sub-units.  As a result, it will cause what is called internalization.  That is, the receptor will be absorbed into the postsynaptic element, and ultimately is destroyed.  Ultimately what this does is decrease the sensitivity in the receptor area.  So, if you’re getting a lot of acetylcholine, you don’t need to have as many receptors to get an effect.   So you don’t need to have as many receptors being made.  Ultimately this decreases the sensitivity when the neurotransmitter no longer is there. 

Muscarinic receptors, on the other hand, use a G protein second messenger system.  We haven’t talked about G proteins yet, but what is important for you to know right now is that there is a wide variety of different second messengers this system uses (and I’ve listed here).  We will talk about those in a little bit more in the next section.

So that’s the acetylcholine type of neuron.  The next type of neuron and neurotransmitter that goes along with signaling is called the GABA receptor and the GABA neurotransmitter.  There’s a wide variety of different GABA receptors but what I’m going to talk about are a couple.   That is the GABAa and the GABAb receptor.

The GABA or gamma aminobutyric acid is synthesized from glutamic acid and it induces what is called IPSPs or inhibitory post synaptic potentials on postsynaptic elements.  In essence, what it does is shuts them down. Again, the GABA acts on two receptors.  The first type is the GABAa receptor.  This is an ionotrophic type of receptor which controls the chloride channel and as you can see here, it has five distinct binding sites. 

The GABA B receptor basically is a metabotrophic receptor and it’s going to control a potassium channel and regulate the system that way. 

Figure 25 kind of is a representation of the GABAa receptor.  As you can see, it has a wide variety of binding sites surrounding a chloride channel (which is going to shut down the system when it’s opened).  GABA will bind on the GABA binding site.  As a result, it causes the chloride channel to open.  The picrotoxin binding site regulates how long that chloride channel stays open.  The benzodiazepine binding site regulates basically the infinity (how much GABA is needed) before that chloride channel actually opens.  Gabamodulin is a linking protein that in essence links the benzodiazepine and GABA binding sites. 

Now there are a variety of other types of neurotransmitters out there as well.  These are classified under what we call the biogenic amines.  As we can see here in slide 27, there is a synthesis that occurs in a variety of different neurotransmitters.  For example, we start with tyrosine which is broken down by tyrosine hydroxylase into l-DOPA).  Then we have Dopa decarboxylase which breaks it down into dopamine, and then dopamine beta hydroxylzse basically breaks it down into norepinephrine.

Dopamine as we can see in slide 28 is used by a wide variety of different systems.  The classic examples are listed here (slide 27) in the nigrostriatal system (which basically projects from the substantial nigra to the caudate nucleus), the mesolimbic system and the mesocortical system.  All of these receptors use a metabotrophic process.  Also, D1 receptors are postsynaptic where D2 receptors are both presynaptic and postsynaptic, so they’re going to be more regulatory.

Norepinephrine is synthesized from dopamine within vesicles.  Here what you have is a variety of structures that are also going to be involved with that.  The classic example is the locus coeruleus which is basically going to give rise to a variety of different norepinephrine fiber systems.  Norepinephrine also intersects with a variety of different receptors, and I’ve just listed a couple of these.  All of these processes and these receptors use a metabotrophic process.  Norepinephrine is extremely, extremely important in relation to depression and other disorders.

The next major system is serotonin.  As we can see here its precursor is tryptofan.  Ultimately, it will be broken down into a variety of other types of substances as well. Serotonin receptors are mostly located in the gut.  And as we can see on slide 31, only about 2% of all seretonin neurons are in the brain.  Of these, a lot of them are located in the brain stem and ultimately go to the cortex.  There’s a variety of different types of systems that go in here and the classic example is the D system which is originating in the dorsal raphe nuclei but doesn’t basically form any synapses.  This is basically a neuromodulation system.  The M system is going to originate from the medium raphe nucleus and ultimately form synapses in a variety of other structures. 

Seretonin release and termination.  First of all basically there’s a variety of different systems that are going to influence seretonin release.  A couple of these are listed on slide 32.  Serotonin termination:  What happens is that seretonin is reabsorbed back into the presynaptic element.  As a result, we can design and develop materials that basically blocks seretonin reuptake.  These are the classic seretonin reuptake inhibitors.  Seretonin is also degraded by mono amine oxidase (MAO)

As you can see in slide 33, there’s also a wide variety of different seretonin receptors Again some of these are ionotrophic and some are metabotrophic. 

The next major neurotransmitter to cover here is glutamic acid or glutamate.  It is an excitatory neurotransmitter and is extremely, extremely important.  It basically interacts with a wide variety of different receptor sites including the NMDA receptor.  Basically this controls a calcium channel.  It also controls a variety of other receptors as well.  These are all important in the area of drug abuse.

The next major system to discuss is peptides.  Peptides are very, very small proteins, usually consist of 30 to 40 amino acids, and there are more than a 100 types.  The last count I think was about 140.  They’re synthesized also in the Soma and transported to the axon terminal or the presynaptic element in vesicles and released.  After the release, these peptides are different from the classic neurotransmitters that we’ve talked about.  That is, they are always degraded and there is no reuptake.  Oftentimes these peptides are co-released with other neurotransmitters and serve as a neuromodulator on receptor sites to indicate how much is out there, or whether you want to down regulate or reabsorb the different receptors back into the postsynaptic element.

Well, this section has kind of covered some basic concepts of receptors and a little bit about their neurochemistry and physiology.  In the next section we’re going to talk about some specific types of receptors and these are called guanine proteins.  This is extremely, extremely important and seems where a lot of metabotrophic types of processes take place.  So until then, we hope that you hang in there and that you’re enjoying your day.