NB2-4 - Neurotransmitters and Synaptic Transmission 1 and DLAs

Question 1

Describe what an electrical synapse is.

Answer 1

It is a synapse where the two neurons communicate via a gap junction

Question 2

Describe the various components of a gap junction.

Answer 2

A gap junction is formed by two opposed connexons which are each composed of six connexins arranged in a circle. Each connexin is composed of four membrane spanning units.

Question 3

Describe the types of chemical synapses and whether they are usually excitatory or inhibitory.

Answer 3

• Axodendritic - commonly excitatory but more proximal contacts are often inhibitory.
• Axoaxonic - commonly inhibitory (diminishes magnitude of AP).
• Axosomatic - commonly inhibitory.
• Tripartite Synapse - with this synapse an astrocyte acts as an intermediary; the astrocyte takes up glutamate released by the presynaptic neuron, converts it into glutamine, and releases the glutamine back to the presynaptic neuron for conversion back to glutamate. The glutamine will then be returned to the presynaptic neuron and converted back to glutamate. Usually excitatory

Question 4

List the two primary types of postsynaptic receptors and describe their basic properties.

Answer 4

Ionotropic Receptors - binding of ligand causes the opening of an ion selective pore.

Metabotropic Receptors - when bound by a ligand these receptors influence coupled G-proteins which will typically start a signal cascade that affects metabolism or gene expression.

Question 5

What is the NMDA receptor? Describe how it functions. What drug interacts with NMDA receptors and what is this drugs affect?

Answer 5

The N-methyl-D-aspartate (NMDA) receptor is an ionotropic glutamate receptor that, once opened, allows cations through (ie - Na+, K+, and Ca++). However, it does not just requrie the binding of glutamate to be opened. It must also bind glycine and the membrane must be depolarized. The membrane must be depolarized to remove the Mg++ and Zn++ ions bound to sites within the channel.

PCP (angel dust) acts as an antagonist to NMDA receptors

Question 6

What are the other glutamate sensitive receptors beside NMDA? How do they differ from NMDA?

Answer 6

AMPA (aka - quisqualate receptor) and the Kainate receptors

Their mechanism of action is similar to that of the NMDA receptor. These ionotropes only allow Na+ and K+ through, however, NOT Ca++

Question 7

List the traditional criteria for a molecule to be considered a neurotransmitter.

Answer 7

1. Synthesized by presynaptic neurons.
2. Stored in preparation for release.
3. Released by presynaptic neurons in a calcium dependent fashion.
4. Specialized receptors (typically postsynaptic) effect stereotyped transmitter- and analogue- dependent physiological changes.
5. Mechanism for removal of transmitter from synapse.

Question 8

List and classify the neurotransmitters we need to know.

Answer 8

Question 9

In which cell types can NTs be synthesized? Why?

Answer 9

Pretty much only within the neurons themselves because the NTs cannot cross the BBB but the precursors for them often can.

Question 10

What are the precursors for the catecholamines, indolamines, NO, GABA, Glycine, Glutamate, and acetylcholine (ACh)?

Answer 10

• Catecholamines - precursor is tyrosine
• Indolamines - precursor is tryptophan
• Glutamate and GABA - precursor is glutamine or α-KG
• Glycine - precursor is 3-phosphoglycerate from glycolysis
• NO - precursor is arginine
• ACh - precursor is acetyl-CoA

Question 11

How are NTs usually stored? Mention important proteins and the different types of vesicles used.

Answer 11

If the NTs are not already present in a vesicle when synthesized, they will be transported into one. This is done by an antiporter that uses a high intravesicular [H+] created by the vesicles H+ ATPase. The antiporter exchanges one proton for one molecule of NT.

Low molecular weight NTs (except NE and Serotonin) are packaged into small clear vesicles that get anchored to the neuron membrane by synapsin near the axon terminal. High molecular weight NTs, NE, and serotonin are packaged into large dense-core vesicles that are anchored farther from the axon terminal.

Question 12

Describe the typical process of NT release.

Answer 12

When the axon terminal deploarizes, calcium enters which activates a calmodulin dependent protein kinase that liberates the vesicle by phosphorylating synapsin. The vesicular v-SNARE proteins synaptobrevin and synaptotagim then bind to the t-SNARE proteins syntaxin and neurexin on the terminal membrane, respectively. These proteins zipper together, pressing the vesicle against the neuronal membrane, and synaptophysin, in the presence of calcium, forms a fusion pore which facilitate fusion of the vesicle the membrane and NT release.

Question 13

Describe how neurons perform vesicle retrievel after NT release.

Answer 13

After a vesicle fuses with the cell membrane and releases its NT, it will be retrieved. This is done via endocytosis. After endocytosis, the small clear vesicles are recycled by endosomes in the axon terminal while the large dense core vesicles are transported retrogradely.

Question 14

What biochemical steps are present in all catecholamine synthesis? Which step is considered the rate limiting one?

Answer 14

The synthesis of Dopamine (DA) occurs before making any catecholamine

1. Tyrosine from either the diet or synthesis from phenylalanine enters the dopaminergic, adrenergic, or noradrenergic neuron.
2. Tyrosine hydroxylase converts tyrosine to L-DOPA
3. DOPA decarboxylase converts L-DOPA to DA
4. DA is then transported into a small clear vesicle for storage or conversion into another catecholamine

It is the conversion of tyrosine to L-DOPA by tyrosine hydroxylase that is the rate limiting step

Question 15

How would a disruption of the axonal MT track affect NT synthesis?

Answer 15

It wouldn’t affect it at first since NT are synthesized near the axon terminal and NT precursors are pumped into the neuron near the axon terminal. However, the enzymes that synthesize the NTs are translated in the soma and transported via the MT tract to the axon terminal. After some time, the amount of NT synethesis enzymes present in the axon terminal will fall and so will NT production

Question 16

What is another name for L-DOPA?

Answer 16

dihydroxyphenylalanine

Question 17

What enzymes break down catecholamines and what do they break them down into? Where are they usually located?

Answer 17

• Monoamine Oxidases (MAOs) break down catecholamines into organic acids, for urinary excretion, and are usually located in the mitochondria of presynaptic neurons and liver cells.
• Catechol-O-methyltransferases (COMTs) break down E and NE into metanephrines, for urinary excretion, and DA into 3-MT which an MAO will further break down into an organic acid for urinary excretion. COMTs are usually found in the postsynaptic neuron or liver cells

Question 18

Describe the synthesis and removal of DA.

Answer 18

1. DA is synthesized and stored in a vesicle for later exocytosis via the usual mechanism (make sure you know this mechanism)
2. DA will be removed from the synaptic space in three different ways:
   
   1. Taken back up into the presynaptic neuron by reuptake-1 transporters where it will be either repacked into a vesicle or degraded by MAOs.
   2. Taken up into the postsynaptic neuron by reuptake-2 transporters where it will be degraded by COMTs
   3. It diffuses into the circulation and is broken down by COMTs and MAOs in the liver.

Question 19

Describe the synthesis and removal of norepinephrine occurring within neurons?

Answer 19

Synthesis - Dopamine is synthesized from tyrosine and transported into a small clear vesicle via the usualy mechanism. In the vesicle, dopamine hydroxylase will convert it into norepinephrine. The vesicle will then be tethered near the terminal for eventual exocytosis.

Removal - reuptake-1 will actively transport NE back into the presynaptic neuron where it will be either reloaded into a vesicle and metabolized by MOA. Reuptake-2 will actively transport NE into the postsynaptic neuron where it will be metabolized by COMT. Any remaining NE will diffuse away into the blood and be metabolized in the liver by both MAO and COMT.

Question 20

Describe the synthesis and removal of epinephrine occurring within neurons?

Answer 20

Synthesis - tyrosine is converted into NE via the usual neuronal mechanism. NE then leaks out of its vesicle into the cytoplasm where PNMT (phenylethanolamine N-methyltransferase) converts it into epinephrine. Epinephrine is then actively transported back into a vesicle which is then stored for later release.

Removal - mechanisms for removal of E are the same as for NE

Question 21

Describe the synthesis and removal of serotonin.

Answer 21

1. Tryptophan is taken up from the plasma by brain cells
2. Tryptophan hydroxylase hydroxylates tryptophan to 5-hydroxy-tryptophan
3. Aromatic amino acid decarboxylase decarboxylates 5-hydroxy-tryptophan to 5-hydroxy-trymptamine (aka - 5-HT or serotonin)
4. Serotonin is then stored in vesicles for eventual exocytosis
5. SERTs (serotonin reuptake transporters) will transport serotonin back into the presynaptic neuron from the synaptic cleft. Concurrently, synaptic serotonin can be metabolized by MAOs to 5-hydroxy-indolacetyldehyde which aldehyde dehydrogenase will convert to 5-hydroxy-indolacetic acid for urinary excretion

Question 22

What are the major amino acid NTs we need to know and are their effects normally excitatory or inhibitory? Where are their receptors usually found in the nervous system?

Answer 22

GABA’s effects are inhibitory and its receptors are ubiquitous in the nervous stem

Glycine’s effects are inhibitory and its receptors are localized primarily within the spinal cord, lower brainstem, and retina.

Glutamate’s effects are strongly excitatory and its receptors are ubiquitous in the nervous system

Question 23

Describe the synthesis and removal of GABA

Answer 23

1. In the mitochondria, glutaminase converts glutamine to glutamate
2. In the cytoplasm, GAD (glutamic acid decarboxylase) uses PLP (Vit B6) to convert glutamate to GABA.
3. GABA is then stored in a vesicle for eventual exocytosis
4. GABA transporters pump GABA either back into the presynaptic neuron or an astrocyte.
5. Once in the presynaptic neuron, GABA is repackaged into the vesicles. Once in the astrocyte, the mitochondrial enzyme, GABA-T, converts GABA to glutamate which is transported to the cytoplasm where glutamine synthetase converts it into glutamine which glutamine transporters than pump out of the astrocyte and back into the presynaptic neuron

Question 24

Describe the synthesis and removal of glycine.

Answer 24

1. The glycolytic intermediate, 3-phosphoglycerate, is used to synthesizie serine in the cytoplasm
2. Serine transhydroxymethylase, in a THF (tetrahydrofolate) dependent manner, converts serine to glycine.
3. Glycine is then stored in a small clear vesicle for eventual exocytosis
4. Glycine transporters in the presynaptic membrane will reuptake glycine from the synaptic cleft

Question 25

Describe the synthesis and removal of glutamate.

Answer 25

1. Glutamate is made in one of two ways:
   
   1. α-KG from Krebs is transaminated into glutamate
   2. In the mitochondria, glutaminase converts glutamine to glutamate
2. It is then stored in vesicles for eventual exocytosis
3. Glutamate transporters move synaptic glutamate to either the presynaptic neuron or an astrocyte.
4. In the presynaptic neuron, glutamate is repackaged. In the astrocyte, glutamine synthetase converts glutamate to glutamine which ist then transported out of the astrocyte and back into the presynaptic neuron

Question 26

What are the key differences between nitric oxide (NO) and other NTs?

Answer 26

NO is a gas which means it is only synthesized when needed (it’s not stored) and it spontaneously decays so it can’t be reused.

Question 27

Describe how the NT NO is synthesized in a neuron and how NO has its effects.

Answer 27

1. A postsynaptic neuron’s NMDA receptor gets activated which allows Ca++ into the cell.
2. Ca++ binds calmodulin
3. The calcium-calmodulin complex activates nNOS (nitric oxide synthase)
4. nNos converts L-arginine to L-citrulline and NO.
5. NO will bind to soluble guanylate cyclase which will increase the [cGMP], triggering a signaling cascade
6. Because NO is freely diffusible, it can leave the post synaptic neuron to exert its affects on nearby cells (ie - presynaptic neuron, glial cells, adjacent neurons)

Question 28

Describe the synthesis and removal of acetylcholine (ACh).

Answer 28

1. Glucose enter axon via facilitated diffusion.
2. Glycolysis generates pyruvate.
3. Pyruvate enters the mitochondria where the PDH complex converts it into Acetyl-CoA; Acetyl-CoA is then transported back to the cytoplasm.
4. ACh transferase then combines acetyl-CoA and Choline (retrieved from the synapse) into ACh. ACh is transported into a small clear vesicle for eventual release into synapse.
5. ACh esterase hydrolyzes ACh into choline and acetate or the ACh is taken up by astrocytes near the synapse. The choline is taken up for re-use by the pre-synpatic neuron

Question 29

Describe how high molecular weight NTs are generally synthesized and stored.

Answer 29

The propeptide and its cleaving enzyme are synthesized in the soma and packaged into a large dense core vesicle by the golgi which is transported to the axon terminal. Propeptides are then cleaved into smaller peptide NTs. The peptide containing vesicles are tethered farther from release sites than the small clear vesicles.

Question 30

Answer 30

A

Blocking the K+ channel prolongs membrane depolarization after an AP

Question 31

Answer 31

E

Question 32

Which nuclei in the brain utilize ACh signaling and what do these nuclei do? Is ACh typically excitatory or inhibitory?

Answer 32

There are two major constellations in the brain that interacts with cholinergic neurons.

1. The basal forebrain constellation, most notably the nucleus of Meynert, which provides innervation to the entire neocortex, amygdala, hippocampus and thalamus.
2. The dorsolateral pontine tegmental constellation which innervates the basal ganglia, thalamus, hypothalamus, reticular formation, and deep cerebellar nuclei.

ACh is typically excitatory

Question 33

What types of receptors are nicotinic receptors? Are they found in the CNS or PNS?

Answer 33

It is an ionotropic receptor that opens when bound by ACh. It allows cations to pass through. These receptors are found in both the CNS and PNS

Question 34

What are autoreceptors and what do they do?

Answer 34

Autoreceptors are receptors present on the presynaptic neuron that, when bound by the NT released by the presynaptic neuron, inhibit the release of more NT by that neuron. This is a type of negative feedback inhibition.

Question 35

List and classify the metabotropic glutamate receptors.

Answer 35

• Group I
  
  • Types 1 & 5 which are typically postsynaptic and excitatory
• Group II
  
  • Types 2 & 3 which are typically autoreceptors
• Group III
  
  • Types 4 & 6-8 which are typically autoreceptors

Question 36

List the types of GABA receptors, describe how they work, and mention the drugs that affect them and how.

Answer 36

GABA_A - an ionotropic receptor that allows Cl- to enter the cell (hyperpolarizing). Barbituates will also open this channel while benzodiazepines will just increase Cl- flow through the channel when GABA is bound

GABA_B - a metabotropic receptor that activates a signaling cascade that results in closure of Ca++ channels and enhancement of K+ channels (hyperpolarizing). These receptors are often found at axoaxonic synapses.

Question 37

Answer 37

E

NMDA antagonsist often cause pscychosis

Barbituate agonists will sedate the patient

Benzodiazepine agonists will calm the patient

Question 38

Describe how an alpha motor neuron regulates its ACh release?

Answer 38

The α-motor neuron axon bifurcates with one terminal synapsing on the muscle and the other terminal synapsing on a renshaw cell (interneuron) that will synapse and release glycine on the soma of the α-motor neuron which will cause Cl- influx and hyperpolarize the soma, making an AP less likely to fire again.

Question 39

What is strychnine and what does it do.

Answer 39

Strychnine is a toxin that causes muscular convulsions and eventual death by asphyxiation. It does this by acting as an antagonist to glycine receptors (but NOT NMDA, AMPA, or Kainate). Since renshaw cells have their inhibitory effects on α-motor neruons via glycine receptors, strychnine blocks this. This is why muscular convulsions are seen. If the toxin reaches the brainstem then the convulsions will lead to asphyxiation.

Question 40

What is the mechanism of action for tetanus toxin and what are its effects?

Answer 40

Tetanus toxin blocks the release of the NTs GABA and glycine, both of which have important inhibitory effects on α-motor neurons. This leads to spastic paralysis (muscle tightening that causes paralysis).

Question 41

Where are dopaminergic neurons located in the nervous system and what do they do? Are they generally excitatory or inhibitory?

Answer 41

DA receptors can be both inhibitory and excitatory and are located at three major constellations:

1. Substantia Nigra whose axons project to the striatum and are therefore involved with movement
2. Ventral tegmental area whose axons profect to the limbic system and are therefore involved with emotion and memory
3. Hypothalamic arcuate nucleus whose axons project to the median eminence and release DA directly into the hypophyseal portal circulation which will travel to the anterior pituitary to inhibit prolactin release
4. The nucleus accumbens which is the pleasure center (which is why DA makes you happy)

Question 42

List and describe the types of DA receptors and what they do?

Answer 42

All DA receptors are metabotropic and there are two main types:

1. D₁ - like
   
   1. D₁ & D₅ which are excitatory and coupled to cAMP signaling
2. D₂ - like
   
   1. D₂, D₃, & D4 which are inhibitory and coupled to cAMP signaling

Question 43

Answer 43

A

Question 44

Which neurons are degenerated in Parkinson’s disease? What NTs are released by these neurons?

Answer 44

The neurons of connecting the red nucleus to the striatum. These are dopaminergic neurons

Question 45

Where are noradrenergic neurons located in the nervous system and what do they do? Are they generally excitatory or inhibitory?

Answer 45

Noradrenergic neurons are both excitatory and inhibitory and are found in two general constellations:

1. Locus ceruleus in the pons whose fibers project to the thalamus, hypothalamus, limbic structures, and cerebral cortex and serve to help modulate arousal, attention, and feeding/emotional behaviors.
2. Reticular formation nuclei at pontomedullary junction whoes fibers project to the nucleus of the solitary tract (NTS) and certain spinal targets

Question 46

List and describe the types of NE receptors and what they do?

Answer 46

All receptors are metabotropic

• α₁ and ß₁ are excitatory
• α₂ and ß₂ are inhibitory although ß₂ receptors will occasionally have excitatory effects

Question 47

Where are seratonergic neurons located in the nervous system and what do they do? Are they generally excitatory or inhibitory?

Answer 47

Serotonergic neurons are both excitatory and inhibitory. They are mostly localized to the raphe nuclei of the medulla, pons, and midbrain. The medullary nuclei will project to the spinal cord (dorsal horn) and brainstem while the pontine and midbrain nuclei will project to the thalamus, limbic system, and cortex. The neurons to the limbic system are involved with emotional states (depression) and the neurons to the spinal cord are involved with sensation of pain.

Question 48

List and describe the types of serotonin receptors and what they do?

Answer 48

There are seven families of serotonin receptors with 6 being metabotropic.

• 5-HT₁ & 5-HT₅ are inhibitory
• 5-HT₂ is excitatory
• 5-HT₄, 5-HT₆, & 5-HT₇ are excitatory
• 5-HT₃ is a cation ionotropic receptor and is excitatory

Question 49

Answer 49

D

Question 50

What are the neuroactive peptides we need to know?

Answer 50

Beta-endorphin and Enkephalin both of which are opioid peptides

Substance P

Question 51

How is beta-endorphin synthesized? What does beta-endorphin do?

Answer 51

1. Proopiomelanocortin (POMC) is synthesized in the pituitary
2. POMC is then transported to periaqueductal grey and noradrenergic nuclei where it will be proteolytically cleaved to beta-endorphin and other peptides

Beta-endorphin binds to the Mu opioid receptors

Question 52

How is enkephalin synthesized and what does it do?

Answer 52

1. Pre-proenkephalin is synthesized in local spinal and caudal bulbar neurons
2. Pre-proenkephalin is cleaved to produce leu- and met-enkephalin

Leu- and met-enkephalin will bind to delta opioid receptors in the medulla and spinal cord and exert inhibitory effects.

Question 53

How is substance P synthesized and what does it do? How are the effects of substance P inhibited

Answer 53

Substance P is synthesized in peripheral unmyelinated nociceptive fibers and is released into the dorsal horn to elicit pain signaling.

The release of serotonin and NE will indirectly inhibit the effects of Substance P be triggering release of enkephalin from enkephalinergic neurons into the same synapse as substance P