Stahl Chapter 1

  1. Review the general structure of the neuron including dendrites, soma and axon. What is the function of each structure?

Soma: This is the cell body, the command center of the nerve which contains the nucleus, and it is set up structurally to receive information from other neurons through dendrites. So dendrites  are the input to a neuron. Output of information from the neuron is through an axon that forms presynaptic terminals as the axon passes by or when it ends.

  1. Where are possible locations for synapses?

The possible locations for synapses are between the axon of one neuron and the dendrite of another (axodendritic), but also between the axon of one cell and the soma of another cell (axosomatic synapse), and between the axon of one neuron and the axon of another (axoaxonic synapse).

  1. Describe classic neurotransmission .

Classic neurotransmission means that there is stimulation of a presynaptic neuron (by a neurotransmitter, light, drugs, hormones, nerve impulses) which causes an ELECTRICAL impulse to be sent down to its axon terminal. These electrical impulses are then converted into CHEMICAL messengers and released to stimulate the receptors of the post-synaptic neuron. Communication within a neuron can be electrical but communication BETWEEN neurons is chemical.

  1. How do retrograde neurotransmission and volume neurotransmission differ from classic neurotransmission?

In retrograde neurotransmission, the second neuron or post-synaptic neuron can actually “talk back” to the presynaptic neuron. Some chemicals are produced specifically as retrograde neurotransmitters like endocannabinoids EC which are synthesized in the postsynaptic neuron. They are released and diffuse to presynaptic cannabinoid receptors. Other retrograde agents are nitric oxide and nerve growth factor which is taken up into vesicles in the presynaptic neuron and taken all the way back to the cell nucelus.

In volume neurotransmission, neurotransmission doesn’t even need a synapse. Because chemical messengers that are sent from neuron A to neuron B might actually spill over to nearby neurons that have a receptor that it is compatible with and interact with it, as long as it’s not destroyed after diffusing from the synapse where it shot out from.

  1. Describe the function of sodium-gated ion channels and calcium gated ion channels in excitation-secretion coupling.

In excitation-secretion coupling, the electrical impulse is changed to the chemical messenger. So first the electrical impulse opens ion channels, the voltage-sensitive sodium channels and the voltage-sensitive calcium channels. So sodium flows into the presynaptic nerve through the channels, and the electrical charge of the action potential moves down the axon until it reaches the presynaptic nerve terminal which causes the CALCIUM channels to open. So then calcium flows into the presynaptic nerve terminal, which causes the synaptic vesicles to spill their chemical contents out of the neuron and into the synapse.

  1. What is a signal-transduction cascade? What are the 2 major targets of signal transduction?

The signal-transduction cascade is what happens after a postsynaptic receptor is stimulated. Two major targets of signal transduction are phosphoproteins and genes.

  1. Describe the sequences of events in the following signal transduction cascades:
  2. G-protein-linked systems:
  • The ligand (neurotransmitter or drug) binds to its receptor.
  • This changes the conformation of the receptor so it fits with the G protein
  • This allows the receptor and G protein combination to be able to bind to an enzyme which will synthesize the second messenger.
  • The enzyme will bind to the G protein and synthesize cAMP (cyclic adenosine monophosphate) which serves as the SECOND messenger.
  • This second messenger cAMP can then activate a THIRD-MESSENGER protein kinase. When protein kinase is activate, this enzyme will be able to phosphorylate other proteins. So it adds a phosphate group to a FOURTH-MESSENGER protein so that it will continue the cascade.
  1. ion-channel-linked systems:
  • A first messenger ligand (neurotransmitter or drug) binds to the receptor of an ion channel,
  • This allows SECOND-MESSENGER ion (such as calcium) to enter, which then activates a sleeping phosphatase enzyme calcineurin
  • Activation of it turns that into a THIRD-MESSENGER active calcineurin (phosphatase).
  • This phosphatase will REMOVE phosphate groups from FOURTH-MESSENGER proteins. So phosphatase and kinase work in opposite ways.

*Adding a phosphate group (phosphorylation) to the fourth messenger phosphoprotein can activate, but for some phosphoproteins, removing a phosphate group (dephosphorylation) can activate it. Activation of a fourth-messenger phosphoprotein can change the synthesis of neurotransmitters, alter neurotransmitter release, change the conductance of ions, and generally maintain the chemical neurotransmission apparatus in either a state of readiness or dormancy. The balance between phosphorylation and dephosphorylation of fourth messenger kinases and phosphatases plays a vital role in regulating many molecules critical to the chemical neurotransmission process.

  1. hormone-linked systems:
  • Certain hormones like estrogen and other steroids can enter right into the neuron
  • Within the cytoplasm of the neuron they can find their receptors and bind them to form a hormone-nuclear receptor complex.
  • The complex can then enter the cell nucleus to interact with hormone response elements (HRE) there to trigger activation of specific genes.
  1. neurotrophin-link systems
  • Neurotrophin activates a bunch of different kinase enzymes to trigger gene expression, which may control such functions as synaptogenesis (making more synapses) and neuronal survival .

* A kinase is just a type of enzyme that attaches a phosphate group to a protein. A phosphatase is an enzyme that removes a phosphate group from a protein

  1. Give examples of second messengers.

For G-protein linked systems: second messenger is a chemical like cAMP

For ion-channel-linked system: second messenger is an ion, like calcium

For hormone-linked systems: second messenger is hormone-nucleur receptor complex

For neurotrophins: A complex set of various second messengers exist, such as proteins that are kinase enzymes.

  1. What is the role of transcription factors?

Transcription factors can turn on genes . The transcription factors themselves get activated by a kinase enzyme (like the third messenger in the g-protein system) that phosphorylates them. Then the transcription factor can bind to the regulatory region of the gene and the gene gets activated.

  1. What is the significance of epigenetics in the understanding of gene expression?

Epigenetic control over whether a gene is read (i.e. expressed) or is not read (i.e., silenced) is achieved by modifying the structure of chromatin. Mylenation etc.

Stahl Chapter 2

  1. List the five targets of psychotropic drugs.

The five targets of psychotropic drugs include

1) 12-transmembrane-region transporter (30% of psychotropic drugs)

2) 7-transmembrane-region G-protein-linked (30% of psychotropic drugs)

3) Enzyme (10% of psychotropic drugs)

4) 4-transmembrane-region ligand-gated ion channel (20% of psychotropic drugs)

5) 6-transmembrane-region voltage-gated ion channel (10% of psychotropic drugs)

  1. Describe agonist spectrum. How does signal transduction change when G-protein-linked receptors are in the presence of:
  1. nothing: In the absence of an agonist, there may still be some conformational change but just at a low frequency. So it’s called constitutive activity and is especially likely to occur in areas where there is a bunch of receptors. So even when each one is working at low frequency, when there are a bunch of them it can still produce detectable signal transduction output. So it’s a small but not truly absent amount of signal transduction
  2. an agonist: An agonist will actually produce a conformation change in the G-protein linked receptor that turns on the synthesis of second messenger to full blast. It’s the action of a full agonist. This can be from the natural occurring transmitter that binds to the receptor, but it can also be some drugs that mimic it exactly. Full blast means the the full array of downstream signal transduction is triggered by a full agonist, so downstream proteins are maximally phosphoryrlated, and genes are maximally impacted. This can either happen by direct-acting agonists that attach directly to the neurotransmitter site, or some drugs can indirectly act to boost the levels of the natural full agonist neurotransmitter. So like a drug that blocks the enzymatic destruction of neurotransmitters (like acetylcholinesterase).
  3. an antagonist (How does an antagonist compare to an inverse agonist?): Also known as a silent or neutral agonist. An antagonist will revert the G-protein-linked receptor back to the place/conformation that it was in when there was nothing attached to it, the constitutive activity. Whether it reverses the action of a full or partial agonist, or an inverse agonist which goes so far as eliminates the constitutive activity.
  4. a partial agonist: A partial agonist produces a conformational change that is about right between the full agonist and the baseline conformation of the receptor (constitutive activity).
  5. an inverse agonist: This kind of agonist causes a conformational change that totally inactivates it and even removes the baseline constitutive activity.
  6. Familiarize yourself with the basic roles of common neurotransmitters.

Acetylcholine is an excitatory neurotransmitter occurring throughout the nervous system. Acetylcholine has many functions ranging from the stimulation of muscles, including the muscles of the gastrointestinal system to vital organs. It is also found in sensory neurons and in the autonomic nervous system and has a part in scheduling the “dream state” while an individual is fast asleep. Acetylcholine plays a vital role in the normal functioning of muscles. For example, the plant poisons, curare, and hemlock cause paralysis of muscles by blocking the acetylcholine receptor sites of myocytes. The well-known poison botulin works by preventing the vesicles in the axon ending from releasing acetylcholine, thus leading to paralysis of the effector muscle.

Acetylcholine (ACh) is found throughout the nervous system. It is the only neurotransmitter that sends and receives information between the motor neurons and voluntary muscles (muscles you have conscious control over, such as the biceps). This means that every move you make depends on the release of ACh from your motor neurons to your muscles to make the move. Some examples include: walking, talking, typing, and even breathing. This neurotransmitter found throughout the body is also distributed often in the brain. In addition to motor, ACh also contributes to attention, arousal, and memory.


Norepinephrine, also known as noradrenaline, is an excitatory neurotransmitter secreted by the adrenal glands. It acts to increase the alertness of the nervous system as well as to stimulate the processes in the body. For example, it is very important in the endogenous production of epinephrine. Norepinephrine has been implicated in mood disorders such as anxiety, in which case its concentration in the body is abnormally high. Alternatively, an abnormally low concentration of it may lead to an impaired sleep cycle.

Norepinephrine (NE) is another neurotransmitter found to regulate behaviour. NE contributes to the modulation of mood and arousal, and is commonly referred to as the stress hormone. When you are in a stressful situation it is NE that is spread all over the body to prepare for the situation. A few examples are as followed: NE increases the amount of oxygen to your brain to allow you to think clearer and faster, NE increases your heart rate to allow more blood to rush to your muscles when you need them, and NE also shuts down metabolic processes for the time of the stressful event so blood and energy that would normally go to the digestive organs can focus on other parts of the body. Scientists refer to this event as ‘Fight or Flight’. Fight or flight is when our body uses NE to prepare us to stay and work through the stressful situation (fight) or run from it (flight).


Also known as adrenaline, epinephrine is an excitatory neurotransmitter produced by the adrenal glands and released into the bloodstream. It prepares the body for the fight or flight reaction. That means that when a person is highly stimulated (fear, anger etc), extra amounts of epinephrine are released into the bloodstream. This release of epinephrine, increases the heart rate, the blood pressure and the glucose production from the liver (glycogenolysis). In this way, the nervous and the endocrine system prepare the body for dangerous and extreme situations. 


Dopamine is considered a special type of neurotransmitter because its effects are both excitatory and inhibitory. It is strongly associated with the reward mechanisms in the brain, and drugs such as cocaine, opium, heroin, and alcohol can temporarily increase its levels in the blood, leading to abnormal firing of nerve cells, which may sometimes manifest as intoxication, or several manners of consciousness/focus issues (such as not remembering where we put our keys, or forgetting what a paragraph said when we have just finished reading it, or simply daydreaming and not being able to stay on task). However, an appropriate secretion of dopamine in the bloodstream plays a role in the motivation or desire to complete a task.

Dopamine (DA) is one of the three most common neurotransmitters found to regulate many different aspects of behaviour, along with norepinephrine and serotonin. DA is used by neurons to make voluntary movements and movements in response to emotion. It also plays a role in the brain’s reward system to help reinforce certain behaviour that result in pleasure/reward. For example, it is due to a surge of DA that prompts us to take that second slice of pizza!

DA is also found to be a crucial factor for providing focus and memory consolidation.


Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter. An abnormally low secretion of GABA may cause conditions like anxiety. Because it is an inhibitory neurotransmitter, GABA acts as a brake to the excitatory neurotransmitters, and thus when it is abnormally low this can lead to anxiety. It is widely distributed in the brain and plays a principal role in reducing neuronal excitability throughout the nervous system.


Glutamate is another neurotransmitter with an excitatory effect and usually ensures homeostasis with the effects of GABA. It is the most common neurotransmitter in the central nervous system; however, excessive levels of it can be toxic to the nerve cells and may lead to conditions like stroke.


GABA  is known as an inhibitory postsynaptic potential (PSP) -- meaning it decreases the likelihood the neuron will fire an action potential. In contrast, glutamate is known as an excitatory PSP -- meaning it increases the likelihood the neuron will fire an action potential. It is due to the firing of an action potential that allows the neuron to open and release the neurotransmitters to carry the messages on. Many of the neurotransmitters such as NE and ACh are versatile as they can produce both inhibitory or excitatory PSPs. GABA and glutamate are different as they exclusively produce one or the other.

GABA and glutamate are the brain’s most plentiful neurotransmitters, with GABA present in approximately 40% of all synapses in the brain and glutamate in over 50%! It may seem odd, but it is very important to have inhibitory PSPs -- it is because of GABA we can stay calm and not overwhelm ourselves. When we get overwhelmed it compromises other processes in our body, such as our ability to think clearly, have an appetite, or sleep. As you can imagine in contrast, it is also crucial to have excitatory PSPs. Glutamate is the neurotransmitter best known for contributing to learning and memory.


Serotonin is an inhibitory neurotransmitter that has been found to be intimately involved in emotion and mood. Adequate amounts of serotonin are necessary for a stable mood, and also to balance any excessive excitatory neurotransmitter effects in the brain. Like norepinephrine, serotonin also regulates many processes in the body, such as carbohydrate cravings, the sleep cycle, pain control, and the digestion of food. An insufficient secretion of serotonin may result in decreased immune system function, as well as a range of emotional disorders like depression, anger control problems, obsessive-compulsive disorder, and even suicidal tendencies.

Serotonin is the last of the three most common neurotransmitters found to regulate behaviour. Serotonin is found to affect/regulate a number of different functions in the body/brain from digestion to mood. The release of serotonin from neurons appear to play a predominant role in the regulation of sleep, wakefulness, and eating behaviours.


Histamine is an excitatory neurotransmitter produced by basophils and is found in high concentrations in the blood. It is involved primarily in the inflammatory responses, as well as a range of other functions such as vasodilation, and regulation of the immune response to foreign bodies. For example, when allergens are introduced into the bloodstream, histamine assists in the fight against these microorganisms causing itching of the skin or irritations of the throat, nose and or lungs. It also plays a role in the wake/sleep cycle, by increasing wakefulness.

****In addition to the above classification, neurotransmitters can also be classified based on their molecular types. Dopamine, adrenaline, noradrenaline, and 5-hydroxytryptamine (the indoleamine serotonin) are classified as monoamines. Glycine, glutamate, and GABA are classed under amino acids.

  1. How is enzyme activity restored in irreversible inhibition?

Well if an inhibitor binds to the enzyme irreversibly, there’s no restoring it as a substrate will not be able to bind to the enzyme so it’s rendered as useless. More synthesis of that particularly enzyme would need to be made to resume activity. Now if it’s irreversible, then if there are enough of those substrates or they have a greater affinity for that particular enzyme than the inhibitor, they can bump it out of place.

(We will discuss Cytochrome p450 interactions, pp46-50, in Module 3.)

Stahl Chapter 3

  1. Discuss the implications of the agonist spectrum in relation to ligand-gated ion channels.

Full agonists change the conformation of the receptor to open the ion channel to MAX width and frequency allowed by that binding site. So then the maximal amount of downstream signal transduction possible occurs. Now if there is a second receptor site present on the channel, that fits a positive allosteric modulator, or PAM, this will open the ion channel even more often than with just a full agonist by itself.

Antagonists will simply stabilize the receptor in the resting state, which is the same as the state of the receptor WITHOUT an agonist. So basically the antagonist is just neutral, or silent. The resting state of an ion channel is not FULLY closed, so there is some degree of ion flow. Again, constitutive activity.

A partial agonist will allow activity somewhere in between that of the channels resting state and
when it has a full agonist on it, depending on what it’s closer to. Sometimes partial agonists are known as “stabilizers” because they have the theoretical capacity to find the stable solution between the extremes of too much full agonist action and too little action.

An inverse agonist at the ligand-gated ion channel causes a conformational change in these receptors that first closes the channel and then stabilizes it in an inactive form. So there’s even less ion flow and consequent signal transduction compared to the resting state/baseline.

  1. Describe ligand-gated ion channels in resting, desensitization and activation states.

Resting state: The ligand-gated ion channels open infrequently with consequent constitutive activity that may or may not lead to detectable signal transduction.

Desensitization is an adaptive state where the receptor just stops responding to agonists even if they bind. This can be caused by prolonged exposure to agonists and may be a way for receptors to protect themselves from getting over-stimulated. If the agonist stays much longer, then the receptor converts from a state of simple desensitization to one of inactivation. This state doesn’t reverse simply upon removal of the agonist like it would in the desensitized state. It takes hours in the absence of the agonist for the channel to revert to the resting state where the receptor is again sensitive to new exposure to agonists.

Example: the drug nicotine stimulates nicotinic cholinergic receptors so much that the receptors will quickly densitize and then become inactivated, requiring HOURS in the absence of the nicotine drug to get back to its resting state.

  1. What are allosteric sites?

Allosteric sites are located on the ligand-gated ion channels and are different than the primary receptor sites where neurotransmitters bind so that “allosteric modulators” can bind there. They’re modulators rather than neurotransmitters cuz they don’t really do anything on their own but work in the presence of a neurotransmitter.

What do allosteric modulators PAM and NAM do on their own and
in the presence of neurotransmitter?

PAMs: Positive allosteric modulators that BOOST what the neurotransmitter does.

NAMS: Negative allosteric modulator that BLOCKS what the neurotransmitter does.

If they bind to their allosteric site while the neurotransmitter is NOT binding to its site, the PAM and NAM don’t do anything. But if the neurotransmitter is present, the PAM causes conformational changes in the ligand-gated ion channel that open the channel even further and more frequently than what happens with the full agonist by itself.

Example: consider one PAM, Benzodiazepine. It BOOSTS the action of GABA. If GABA (neurotransmitter) binds to GABA-a receptor site at ligand-gated chloride ion channel, it’s gonna increase chloride ion influx by opening the ion channel. But if a benzo goes on its allosteric site at the same time, then the ion channel is gonna be opened even wider and more frequently. It’s acting like a full agonist at the PAM site. And this is why it works as an anxiolytic, hypnotic, anticonvulsant, amnestic and muscle relaxant, because it enhances GABA’s ability to do these things.

If the NAM binds to the allosteric site while the neurotransmitter is on its agonist binding site, the NAM causes conformational changes in the ligand-gated ion channel that block or reduce the actions that would occur if the neurotransmitter was alone. An example is a benzodiazepine inverse agonist. They have the opposite action of benzodiazepine full agonists and so they diminish chloride conductance through ion channel so much that they can actually cause panic attacks, seizures and some improvement in memory, which is the opposite clinical effect of a benzodiazepine full agonist.

The same allosteric site can accommodate either a PAM or a NAM.

  1. What does the ionic filter do in voltage-sensitive sodium channels (VSSC)?

Each subunit of a voltage-sensitive ion channel has an extracellular amino acid loop between transmembrane segment 5 and 6. This section of amino acids serves as an “ionic filter” and is located in a position so that it can cover the outside opening of the pore. This is like a colander configured molecularly to allow only sodium ions to filter through the sodium channel.

In voltage-sensitive calcium channels (VSCC)?

And in voltage-sensitive calcium channels it only allows calcium channels to filter through.

  1. Describe the role of voltage-sensitive ion channels in neurotransmission:

A nerve impulse is generated in the presynaptic neuron, and the action potential is sent along the axon through voltage-sensitive sodium channels until it reaches voltage sensitive calcium channels that are linked to synaptic vesicles full of neurotransmitters in the axon terminal. Opening of the voltage-sensitive calcium channel and consequent calcium influx causes neurotransmitter release into the synapse. Arrival of neurotransmitter at postsynaptic receptors on the dendrite of the postsynaptic neuron triggers depolarization of the membrane in THAT neuron, and then the signal propagates.

  1. Describe the sequence of events in excitation-secretion coupling:

As the nerve impulse arrives in the axon terminal, it first hits the VSSC as a wave of positive sodium charges delivered by the openings of upstream