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PCOL3922 > Neurotransmitters and neuropeptides > Flashcards

Neurotransmitters and neuropeptides Flashcards

1
Q

What are monoamines and what is their structure?

A 
•	Monoamines- class of neurotransmitters
o	Monoamine neurotransmitters contain one amino group connected to an aromatic ring by a two-carbon chain
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2
Q

What are neurotransmitters?

A

 Neurotransmitters- chemical signals released from a cell (usually from a synapse) to signal one or more other cells

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3
Q

What are different classes of neurotransmitters?

A
  • Amino acids
  • Peptides
  • Quatemary amines
  • Purinergics
  • Lipid metabolites
  • Biogenic amines
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4
Q

Give examples of amino acid neurotransmitters

A

• Amino acids
o Glutamate- excitatory neurotransmitter
o Glycine
o GABA- inhibitory neurotransmitter

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5
Q

Give examples of peptide neurotransmitters

A

o Opioids: enkephalins
o Vassopressin
o Somatostatin

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6
Q

Give an example of quatemary amine neurotransmitters

A

o Acetylcholine

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7
Q

Give an example of purinergic neurotransmitters

A

o ATP

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8
Q

Give an example of lipid metabolite neurotransmitters

A

o Anandamide

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9
Q

Give examples of biogenic amines and their different classes

A 
o	Catecholamines
	Noradrenaline 
	Adrenaline
	Dopamine
o	Indoleamine
	Serotonin
o	Imidazoleamine
	Histamine
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10
Q

What is the general role of monoamines?

A

o Function in the brain to regulate cognitive processes such as emotion, arousal and certain types of memory

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11
Q

What CNS disorders do monoamine drugs treat?

A

o Drugs that alter monoamine neurotransmission are used to treat psychiatric and neurological disorders, including depression, anxiety, schizophrenia and Parkinson’s disease

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12
Q

Describe what monoamine neurotransmitters are usually synthesised from and how this synthesis occurs

A

o Synthesised from decarboxylated amino acids
o Synthesis is mainly catalysed by cytosolic enzymes
 The type of enzyme present in a typical neuron is what determines what type of monoamine is produced and henceforth the function of the cell

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13
Q

What receptors do monoamines usually activate and why does this make them good drug targets?

A

o Monoamines mostly activate G-protein coupled receptors

 Desirable drug target as means that slow metabotropic neurotransmission is being modulated, which is considered safer

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14
Q

Where are monoamines anatomically distributed?

A

o Characteristic anatomical distribution: synthesis is limited to a few restricted sub cortical or brainstem regions, which project to multiple cortical and limbic target regions

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15
Q

Describe the process of catecholamine synthesis

A

 L-tyrosine-> through tyrosine hydroxylase (cytoplasmic rate limiting), L-dihydroxyphenylalanine (L-DOPA) is produced through addition of a hydroxyl group-> through aromatic L-amino acid decarboxylase (DOPA decarboxylase, cytoplasmic), dopamine is produced->through dopamine beta-hydroxylase (vesicular), noradrenaline is produced through addition of a hydroxyl group-> through phenylethanolamine N-methyl-transferase (PNMT, cytoplasmic), adrenaline is produced by addition of a methyl group

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16
Q

Describe the process of indoleamine synthesis

A

o Indoleamines
 Both L-tryptophan and 5-HTP can cross the blood brain barrier, but not 5-HT
 L-tryptophan-> through tryptophan hydroxylase (cytoplasmic, rate limiting), 5-Hydroxy-L-tryptophan (5-HTP) is produced-> through aromatic L-amino acid decarboxylase (DOPA decarboxylase, cytoplasmic), 5-hydroxytryptamine (5-HT, serotonin) is produced

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17
Q

How are monoamines stored and how do they get to that storage space?

A

o Active transport into vesicles via vesicular monoamine transporter (VMAT)
 Transporter in the membrane of the vesicles and it is non-selective
• Any molecule with structural similarity to monoamines can pass through these transporters
o Stored as bound complex with ATP, protein (chromogranin-like), Ca2+, Mg2+ which prevents them from getting out of the vesicle
o The concentration of the neurotransmitter that gets stored in the vesicle is extremely high (About 1.1 M)

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18
Q

What causes monoamine release and how is it done?

A

channels
o Calcium enters the cell which promotes fusion of vesicles to terminal membrane
o Exocytosis of monoamines from their vesicles occur
o Note: some monoamines can also be released extrasynaptically
 E.g. 5HT

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19
Q

What are the types of dopamine receptors and describe their role

A 
o	Dopamine receptors
	G-protein coupled receptors (GPCRs, metabotropic)
	D1-like (D1, D5)
•	D1-like mainly excitatory
	D2-like (D2, D3, D4)
•	D2-like mainly inhibitory
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20
Q

What are the types of adrenoceptors and describe their role and their differential affinity to adrenaline and noradrenaline

A 
o	Adrenoceptors
	G-protein coupled receptors (GPCRs, metabotropic)
•	Alpha-adrenoceptors
o	Alpha1, alpha2
•	Beta-adrenoceptors
o	Beta1, Beta2 and Beta3
	Adrenaline: affinity B2> B1/B3/alpha
	Noradrenaline: affinity alpha> B1>>B2
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21
Q

What are the types of serotonin receptors, their roles, their tropic type and their classification criteria

A

o Serotonin receptors
 Classified (1992) according to:
• Cloned sequence
• Signal transduction mechanisms
• Pharmacological specificity
 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6, 5HT7
 Subtypes: 5HT1A, 1B, 1D, 1-like, (1E), 1F, 2A, 2B, 2C
 5HT3 receptors are ionotropic, the rest are metabotropic
 5HT1 receptors mediate inhibition, the rest mediate excitation

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22
Q

How does monoamine reuptake occur?

A

o Reuptake
 Active transport into neurons via high affinity Na+ dependent membrane transporter proteins: DAT, NAT and SERT
 Main mechanism for terminating monoamine synaptic action

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23
Q

How does monoamine degradation generally occur?

A

 Cytoplasmic monoamines are broken down by monoamine oxidase (MAO) via oxidative deamination

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24
Q

Where is monoamine oxidase bound and what are its two isoforms? What do they degrade?

A

 MAO is bound to mitochondria
 MAO isoforms:
• MAO-A degrades 5-HT, NA, A and DA
• MAO-B degrades DA

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25
Q

Describe how dopamine degradation occurs

A

• Dopamine
o Breakdown process 1-
 Catechol-O-methyl transferase (COMT) breaks dopamine down into 3-methoxytyrosine (3-MT)
 3-methoxytyrosine (3-MT) is broken down into homovanillic acid (HVA) by monoamine oxidase and aldehyde dehydrogenase
o Breakdown process 2
 Dopamine is broken down into 3,4-dihydroxyphenyl-acetic acid (DOPAC) by monoamine oxidase (MAO) and aldehyde dehydrogenase
 3,4-dihydroxyphenyl acetic acid (DOPAC) is broken down into homovanillic acid (HVA) by COMT (catechol-O-methyl transferase)

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26
Q

Describe how noradrenaline degradation occurs

A

o Breakdown process 1-
 Nodadrenaline is broken down into normatadrenaline by catechol-O-methyltransferase (cytoplasmic)
 Normatadrenaline is broken down into MOPGAL by MAO-A
 MOPGAL is broken down into vanillylmandelic acid (VMA) by aldehyde dehydrogenase
o Breakdown process 2-
 Noradrenaline is broken down into DOPGAL by MAO-A (cytoplasmic)
 DOPGAL is broken down into DOMA by aldehyde dehydrogenase
 DOMA is broken down into vanillylmandelic acid (VMA) by COMT

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27
Q

Describe how serotonin degradation occurs

A

 Monoamine degradation
• Serotonin
o Serotonin (5-HT) is broken down into 5-hydroxyindole acetaldehyde by monoamine oxidase
o 5-hhydroxyindole acetaldehyde is broken down into 5-hydroxyindole acetic acid (5-HIAA) by aldehyde dehydrogenase

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28
Q

Why is urine so useful in detecting monoamine turnover in the periphery and what could this be used for?

A

 Breakdown products are excreted in urine
• Therefore, urine can be used as a diagnostic tool for looking at monoamine turnover in the periphery- e.g. tumours will produce excessive amounts of monoamines

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29
Q

What CNS disorders are affected by monoamine storage/release? Specify the type of neurotransmitter for each disorder

A
  • Substance use disorder (DA)
  • Parkinson’s disease (loss of DA neurons in substantia nigra)
  • Schizophrenia (DA)
  • Depression (NA, 5-HT)
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30
Q

What CNS functions and diseases are monoamines involved in?

A
  • Mood
  • Anxiety
  • Schizophrenia
  • Reward
  • Drug abuse
  • Movement
  • Pain
  • Regulation of autonomic function
  • Regulation of hormone release
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31
Q

Describe where dopamine is anatomically produced and the dopamine pathways of the brain

A

o Dopamine is produced at the substantia nigra, the ventral tegmental area and the hypothalamus
o Goes to the:
 Nigrostriatal pathway
• Goes from substantia nigra to the striatum through the thalamus
• Affected by Parkinson’s disease
 Mesolimbic pathway
• Reward pathway
• Starts in the ventral tegmental area and projects to amygdala, hippocampus and nucleus accumbens
 Tubero-hypophyseal pathway
• Starts in ventral tegmental area and goes to the hypothalamus, infundibulum and pituitary gland
• Hormonal regulation
 Mesocortical pathway
• Starts in ventral getmental area and projects to frontal cortex
• For high order cognitive processes

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32
Q

Describe where noradrenaline is anatomically produced and the noradrenaline pathways of the brain

A

• Noradrenaline pathways
o Noradrenaline is produced at the locus coeruleus and reticular formation
o From reticular formation:
 Projects down to spinal cord and affects pain
o From locus coeruleus
 Projects to amygdala, hypothalamus, thalamus, septum, cerebellum and cortex
 Affects movement

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33
Q

Describe where serotonin is anatomically produced and the serotonin pathways of the brain

A

• Serotonin pathways
o Serotonin produced in raphe nuclei
o Projects to spinal cord to modulate pain
o Projects to hippocampus, amygdala, hypothalamus, thalamus, striatum, septum, cerebellum and cortex

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34
Q

What are the transduction mechanisms of dopamine D1-like receptors, their receptor-mediated actions and their drug targets?

A

Type: D1-like (D1, D5)

Transduction mechanisms: Mainly Gs coupled- increase adenylate cyclase activity to increase cyclic AMP

Receptor-mediated actions:

  • Reward
  • Movement
  • Hormone regulation

Important drug targets:
-D1/D2 agonist apomorphone for Parkinson’s disease

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35
Q

What are the transduction mechanisms of dopamine alpha2 receptors, their receptor-mediated actions and their drug targets?

A

Type: alpha2

Transduction mechanisms: Gi coupled: inhibit cAMP and Ca2+, K+ conductance

Receptor-mediated actions: Inhibitory

  • Controls release of many neurotransmitters
  • Attention
  • Mood and anxiety
  • Centrally mediated control of autonomic functions
  • Arousal and vigilance

Important drug targets:

  • Clonidine is a partial agonist used in the treatment of blood pressure
  • Mirtazepine and mianserin are alpha2 antagonists used in the treatment of depression
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36
Q

What are the transduction mechanisms of serotonin 5-HT1 receptors, their receptor-mediated actions and their drug targets?

A

Type: 5-HT1 (1A, 1B, 1D, 1E, 1F, 1-like)

Transduction mechanisms:
Mainly Gi coupled decrease adenylate cyclase activity to decrease cyclic AMP

Receptor-mediated actions:

  • Hallucinations partly via 5HT1-induced disinhibition
  • Hypothermia (1A)
  • Centrally mediated hypotension (1A)
  • Mood: anxiety and depression (1A, 1B and 1D)
  • Sexual behaviour (1A, 1B)
  • Food intake (1A, 1B)
  • Extracerebral vasoconstriction (1B, 1D)
  • Cerebral vasoconstriction (1D)

Important drug targets:

  • 5-HT1A agonist buspirone for anxiety
  • 5-HT1D agonist sumaptriptan for migraine
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37
Q

What are the transduction mechanisms of serotonin 5-HT3 receptors, their receptor-mediated actions and their drug targets?

A

Type: 5-HT3
Transduction mechanisms: Ligand-gated ion channel- conducts Na+

Receptor-mediated actions:

  • Mesolimbic DA release-> increase reward and drug withdrawal effects
  • Centrally mediated modulation of gastrointestinal function
  • Mediates vomit reflex via area postrema in medulla
  • Nociception

Important drug targets:
5-HT3 antagonist ondansetron for antiemesis

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38
Q

What are the transduction mechanisms of serotonin 5-HT4 receptors, their receptor-mediated actions and their drug targets?

A

Type: 5-HT4

Transduction mechanisms: Mainly Gs coupled
-Increase adenylate cyclase activity to increase cyclic AMP

Receptor-mediated actions: -Increase striatal DA release- cognitive performance
-Stimualte peristalsis in GIT

Important drug targets:

  • 5-HT4 agonist cisapride for gastroesophageal reflux
  • 5-HT4 agonist tegasarod for irritable bowel syndrome
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39
Q

What are the transduction mechanisms of adrenoceptors alpha1 receptors, their receptor-mediated actions?

A

Type: Alpha1

Transduction mechanisms: Gq coupled: IP3 activation and calcium mobilisation; DAG activation and PKC to phosphorylate cellular proteins
Gi coupled: inhibit cAMP and Ca2+, K+ conductance

Receptor-mediated actions: Mainly excitatory:

  • Attention
  • Mood and anxiety
  • Centrally mediated control of autonomic functions
  • Arousal and vigilance
40
Q

What are the transduction mechanisms of adrenoceptors alpha 2 receptors, their receptor-mediated actions and their drug targets?

A

Type: Alpha2

Transduction mechanisms: Gi coupled; inhibit cAMP and Ca2+, K+ conductance

Receptor-mediated actions:
Inhibitory
-Controls release of many neurotransmitters
-Attention
-Mood and anxiety
-Centrally mediated control of autonomic functions
-Arousal and vigilance

Important drug targets: -Clonidine is a partial agonist used in the treatment of blood pressure
-Mirtazepine and mianserin are alpha2 antagonists used in treatment of depression

41
Q

What are the transduction mechanisms of adrenoceptors beta1 and beta 2 receptors, their receptor-mediated actions?

A

Type:Beta1 and Beta2

Transduction mechanisms: Gs coupled: cAMP and PKA to phosphorylate cellular proteins

Receptor-mediated actions: Excitatory- as per alpha1

42
Q

What are the transduction mechanisms of serotonin 5-HT2 receptors, their receptor-mediated actions?

A

Type: 5-HT2 (2A, 2B, 2C)

Transduction mechanisms: Mainly Gq coupled-increase phospholipase C activity to increase IP3/DAG

Receptor-mediated actions: -Increased prolactin and corticotrophin release from hypothalamus (2A, 2C)

  • Choroid plexus CSF production (2C)-Hallucinations partly via cortical excitation (2A, 2B, 2C)
  • Regulation of sleep (2A)
  • Mood: anxiety and depression (2A)
  • Sexual behaviour (2A)
  • Food intake (2C)
  • Vasodilation (2 to NO)

Important drug targets:

  • 5-HT2A, 2C antagonists pizotifen and mianserin for migraine prophylaxis
  • 5-HT2A antagonist clozapine for antipsychosis
43
Q

What are drugs that affect monoamine synthesis and what are they used for?

A

o 5-HTP used (self-medication) to treat depression, anxiety and insomnia
 Limited research to how safe and effective 5-HTP is as a supplement
o L-DOPA is used in Parkinson’s disease to increase the synthesis of dopamine in the substantia nigra

44
Q

Does dietary tryptophan increase 5-HT synthesis? Discuss

A

o Dietary tryptophan increases 5-HT synthesis
 Egg whites, fish, cheese and soy beans contain high amounts of tryptophan, but the transport mechanism that carries tryptophan across the blood brain barrier equally transports other large neutral amino acids that are contained in those foods
 Unlikely that you’d be able to modulate positive mood by diet
 Evidence that taking tryptophan supplements can reduce stress and elevate mood only in vulnerable individuals

45
Q

Why are intermediaries targeted as potential therapeutics to increase desired monoamine production?

A

o Target intermediaries as they are past the rate limiting step, and hence if these intermediaries are boosted than the monoamines they produce would be boosted as well

46
Q

What drugs are used to affect monoamine storage and release? Describe their mechanism and uses

A

o Amphetamine derivatives are substrates for VMAT
 E.g. MDMA, dexamphetamine, methamphetamine
• MDMA used to be clinically used for therapy, but now no longer used
o Concerns with overuse triggering psychotic episodes and schizophrenia
o Compete with monoamines for vesicular storage
o Increased cytoplasmic endogenous monoamine increases spontaneous leakage into the synapse
o Amphetamine (e.g. Adderall) is used in the treatment of ADHD and narcolepsy

47
Q

What are recreational drugs that target monoamine reuptake and how do they work?

A

• Drugs that target reuptake
o Recreational:
 Cocaine blocks DAT, NAT and SERT
 Amphetamines compete with monoamines at DAT, NAT and SERT

48
Q

What are antidepressants that target monoamine reuptake and how do they work?

A

 Tricyclic antidepressants (TCA) block NAT and/or SERT more than DAT
 Noradrenaline reuptake inhibitors (NRI) block NAT
 Serotonin noradrenaline reuptake inhibitors (SNRI) block SERT and NAT
 Selective serotonin reuptake inhibitors (SSRI) block SERT
 Bupropion (zyban) is an atypical antidepressant: blocks NAT, DAT. Promotes release of NA, DA (noradrenaline dopamine releasing agent- NDRA). Anti-nicotinic. Many metabolites
• Try not to affect dopamine pathway as it affects the reward pathway- can lead to addiction
• Only licensed as a smoking addiction aid in Australia

49
Q

What are examples of drugs that target monoamine degradation and what are they used for?

A

• Drugs that target degradation
o Monoamine oxidase inhibitors (MAOIs) are used clinically
o Selective MAO-A and non-selective MAO inhibitors used in treatment of depression
o Selegiline is an MAO-B inhibitor used in the treatment of Parkinson’s disease
 Mostly used alongside L-DOPA treatment to increase dopamine through precursor treatment and inhibiting degradation

50
Q

Describe the history of dopamine’s discovery and description

A

• Dopamine
o 1910- first synthesised by George Barger and James Ewens
o 1957- First identified DA in the human brain by Kathleen Monagu
o 1957-1962- Nils-Ake Hillarp and Arvid Carlsson demonstrated that DA acts as a neurotransmitter, not just precursor for NA and adrenaline
o 2000- Arvid Carlsson awarded the Nobel prize in physiology or Medicine for his contributions in discovering DA’s role as a neurotransmitter, its function in controlling movement, and its role in Parkinson’s disease

51
Q

Describe the history of serotonin’s discovery and description

A

• Serotonin
o 1935- Vittoria Erspamer detected a previously uknown amine in enterochromaffin cells
o 1937- Erspamer named the newly discovered amine “enteramine”
o 1948- Maurice M. Rapport, Arda Green and Irvine Page discovered a vasoconstrictor in blood serum and called it serotonin
o 1952- Enteramine and serotonin were discovered to be the same substance. The abbreviation of the chemical name 5-hydroxytryptamine, 5-HT, became the preferred name
o 1953- Betty Twarog discovered serotonin in the central nervous system

52
Q

Describe the history of adrenaline/noradrenaline’s discovery and description

A

• Adrenaline/noradrenaline
o 1895- Napoleon Cybulski first to isolate adrenaline from adrenal gland
o 1900- Jokichi Takamine and keizo uenaka independently discover adrenaline
o 1901- Takamine first to isolate and purify adrenaline from animal glands
o 1904- adrenaline first synthesised by Friedrich Stolz
o 1946- Ulf von Euler first identified noradrenaline in the brain

53
Q

What is a neuropeptide and its composition?

A

• Neuropeptide- a small protein or polypeptide that acts as a neurotransmitter in the nervous system
o Linear polymer made up of amino acids joined by peptide bonds
o Some neuropeptides also act as hormones (e.g. oxytocin or vasopression)

54
Q

Where are neuropeptides found?

A

o Found in CNS and peripheral nervous system

55
Q

How many known peptides are there in the brain?

A

o There are more than 100 known neuropeptides in the brain

 More neuropeptides await discovery

56
Q

Describe the neuropeptides in the calcitonin family

A

Calcitonin

Calcitonin gene-related peptide

57
Q

Describe the neuropeptides in the hypothalamic hormones family

A

Oxytocin

Vasopressin

58
Q

Describe the neuropeptides in the hypothalamic releasing and inhibitory hormones family

A 
Corticotropin-releasing factor (CRF or CRH)
Gonadotropin-releasing hormone (GnRH)
Growth hormone-releasing hormone (GHRH)
Somatostatin
Thyrotropin-releasing hormone
59
Q

Describe the neuropeptides in the Neuropeptide Y family family

A 
Neuropeptide Y (NPY)
Neuropeptide YY (PYY)
Pancreatic polypeptide (PP)
60
Q

Describe the neuropeptides in the Opioid peptides family

A

B-endorphin (also a pituitary hormone)
Dynorphin peptides
Leu-enkephalin
Met-enkephalin

61
Q

Describe the neuropeptides in the Pituitary hormones family

A 
Adrenocorticotropic hormone (ACTH)
Alpha-melanocyte-stimulating hormone (alpha-MSH)
Growth hormone (GH)
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
62
Q

Describe the neuropeptides in the Tachykinins family

A

Neurokinin A (substance K)
Neurokinin B
Neuropeptide K
Substance P

63
Q

Describe the neuropeptides in the VIP-glucagon family family

A

Glucagon
Glucagon-like peptide-1 (GLP-1)
Pituitary adenylate cyclase-activating peptide (PACAP)
Vasoactive intestinal polypeptide (VIP)

64
Q

Describe the neuropeptides in the Some other peptides family

A 
Agouti-related peptide (ARP)
Bradykinin
Cholecystokinin (CKK:multiple forms)
Cocaine-and amphetamine-regulated transcript (CART)
Galanin
Ghrelin
Melanin-concentrating hormone (MCH)
Neurotensin
Orexins (or hypocretins)
Orphanin FQ (or nociception) (also grouped with opioids)
65
Q

What are ways to determine the effects of neuropeptides?

A

o Using selective agonists or antagonists to define cellular and behavioural effects
o Knock-out animals
o Peptidase inhibitors

66
Q

How can selective agonists or antagonists be used to determine the effects of neuropeptides, describe how it was used to determine opioid effects and what are possible limitations/considerations of this approach

A

o Using selective agonists or antagonists to define cellular and behavioural effects
 Agonists- define what activation of the receptor can do
• Informs what the system is important for but not what endogenous opioids are doing
• E.g. endogenous opioids are involved in pain relief, euphoria, constipation, respiratory depression
 Antagonists- small molecule lipophilic drugs developed for opioid receptors (effects at a behavioural level)
• E.g. 1970- electrical stimulation produced analgesia (central/periaqueductal gray) reversed by opioid antagonists (naloxone) implicating endogenous opioids
 Determining action has been hindered by poor antagonists and improper use of inverse agonists
• Effect the antagonist is reversing is the effect of the endogenous peptide
• Inverse agonists- dull down native activity of the receptor that is occurring when no agonist is present and blocks action of agonist
o However, inverse agonists inform what occurs when receptors are turned off, not necessarily the effect of the endogenous agonist

67
Q

How can knock-out animals be used to determine the effects of neuropeptides, describe how it was used to determine opioid effects and what are possible limitations/considerations of this approach

A

o Knock-out animals
 Knock out production of the neuropeptide or receptor
• E.g. enkephalin knockouts are highly anxious, fearful, have altered sexual activity, changes in food palatability
 If this produces a behaviour phenotype, can infer that peptide of interest is important for this
 Limitation
• Compensation can occur if knockout occurs during development
o Although this is less of a problem with conditional knockouts

68
Q

How can peptidase inhibitors be used to determine the effects of neuropeptides, describe how it was used to determine opioid effects

A

o Peptidase inhibitors
 Breakdown neuropeptides
 Can see what happens when endogenous peptide is boosted
 E.g. inhibiting enkephalin-degrading enzymes produces antinociceptives, antidepressant, and anxiolytic effects in rodents

69
Q

Describe the process of neuropeptide synthesis

A

• Requires transcription and translation
• Many steps that can be regulated which can result in one gene producing different peptides
• Process
o Transcription of mRNA
o Mature mRNA translated on the ribosome to an inactive prepropeptide
o N-terminal cleavage by peptidase results in propeptide
o Propeptide is packaged into dense core vesicles (DVC) in the trans-golgi network
 DCVs (probably about 10 000 peptide molecules/vesicle) vs SCV
 Neurons have DCV and SCVs
o In the DCV peptide undergoes post-translational processing

70
Q

Do dense core vesicles only contain one type of neuropeptide?

A

 Some neurons contain many neuropeptides- many types of different peptides can go into one dense core vesicle

71
Q

Describe the release of neuropeptides and the requirements for this release. Describe the location and time frame of this release.

A

 Dense core vesicles are released at sites away from synaptic cleft
• Need a lot of calcium entry to trigger calcium release as they are not in active zone of the synapse where there are a lot of calcium channels
o Differences in Ca2+ sensor location and sensitivity of release
• Terminal, axonal or dendritic release: lots of release is non-synaptic which means that release may require different proteins
o However, only a small number of DCVs in terminal and may take hours to replenish
 This may limit their role to do short bursts of activity
• Movement from the cell body can be regulated by neuronal activity

72
Q

What type of receptors are neuropeptide receptors?

A

 Neuropeptide receptors are mainly G-protein coupled receptors

73
Q

Can neurotransmitters or neuropeptides travel greater distances?

A

 Neuropeptides may spread large distances (um or longer vs nm for neurotransmitter)

74
Q

Why can neuropeptides be effective at long distances from their release site?

A

• Receptors have high affinity to neuropeptides
 Neuropeptides may spread large distances (um or longer vs nm for neurotransmitter)
• This is because the neuropeptide is released at unusual sites
• Distant effects

75
Q

Are neuropeptides specific to certain receptors? Describe

A

• Some neuropeptides act at multiple receptors and some receptors have multiple peptide agonists
o May act on auto-receptors (located on cell that is releasing neuropeptide), post-synaptic or extra-synaptic receptors
o Receptors may be internalized and keep signalling within the cell

76
Q

How are neuropeptides discarded from the extracellular space?

A

 There is no neuropeptide reuptake-neuropeptides need to be resynthesised
• The neuropeptides are broken down by extracellular peptidases

77
Q

What are the 3 opioid propeptide families?

A

 POMC
 Pro-enkephalin
 Pro-dynorphin

78
Q

Describe the POMC opioid peptide in terms of:

  • Length
  • Content
  • Site of production
  • Response type/distance
A

• Long propeptide
• Broken up into range of different peptides
o Opioid is B-endorphin
 Large peptide with signature opioid agonist motif at its beginning
• Almost all POMC in brain is made in neurons in hypothalamus
o When hypothalamus is producing B-endorphin, it will be released in a variety of places in the brain
 Coordinated response-activate one region and release multiple peptides

79
Q

Describe the pro-enkephalin opioid peptide in terms of:

  • Length
  • Content
  • Site of production
  • Response type/distance
A

 Pro-enkephalin
• Methionine enkephalin or leucine enkephalin
o Cleavage in multiple methionine enkephalin and one leucine enkephalin
 Leucine-enkephalin and met-enkephalin only have the signature opioid agonist motif
• Enkephalin- distributed expression
o Enkephalin expression/effects are local

80
Q

Describe the pro-dynorphin opioid peptide in terms of:

  • Length
  • Site of production
  • Response type/distance
A 
	Pro-dynorphin
•	Dynorphin A
•	Dynorphin B
•	Longer peptides 
•	Expression is distributed
o	Expression/effects are local
81
Q

What is the amino acid sequence of the signature opioid agonist motif?

A

Tyr-Gly-Gly-Phe-Leu/Met

82
Q

Where are opioid receptors located in the brain?

A

o Opioid receptors are expressed throughout the brain

83
Q

What are the 3 main types of opioid receptors, what is their structure and G proteins?

A

 There are 3 types of opioid receptors
• Mu (μ), delta(δ) and kappa(κ) receptors
o All Gi/G0 receptors
o 7 transmembrane receptor

84
Q

What effects can occur when opioids bind to their receptors?

A

• Binding of these opioids to receptors will activate potassium channels, inhibit neurotransmitter release, inhibit calcium channels and inhibition of adenyl cyclase (affecting cAMP level)

85
Q

How are opioid peptides degraded?

A 
o	Opioid peptide degradation
	Several peptidases cleave opioid peptides through signature opioid motif 
•	Aminopeptidase
•	Neutral endopeptidase
•	Dipeptidyl carboxypeptidase
86
Q

Which opioid propeptide is most affected by degradation and what is the effect of this?

A

 Enkephalin more susceptible to peptidases than other opioid peptides-thought that actions of peptidase inhibitors are due to regulation of enkephalin breakdown

87
Q

Describe the effect of endogenous opioids

A
  • Gastrointestinal function
  • Pain perception
  • Drug addiction/reward
  • Fear response
  • Stress response
  • Attachment formation
  • Decision making
  • Mood

o Opioids can regulate many actions
 Glutamate release
 GABA release
 Post-synaptic activity

88
Q

Explain why endogenous responses are scarce at differing levels of stimulation when looking at responses at a cellular level and how this can be studied

A

• There are a lot of cellular effects of agonists but endogenous responses are scarce-> may need high stimulation-> high frequency stimulation effects suggests a role in learning events
o Can use agonists and peptidase inhibitors to study cellular actions
o Studying slower actions harder than fast neurotransmitters like glutamate
o Hypohysis- need huge amounts of calcium entry to get release of neuropeptides
 Need high stimulation-> only effective at high stress events
 However, peptide action at typical CNS synapse may differ to neurohypophysis
o However, endogenous opioids can be released with low stimulation but their actions are prevented by peptidases
o Moderate stimulation means that enough enkephalin is released that the peptidases are overwhelmed

89
Q

Why are peptide drugs not great drugs?

A

• Peptide drugs are not great drugs due to proteolysis and difficulty crossing blood brain barrier-> non-peptide drugs necessary

90
Q

Describe two examples of opioid agonists/antagonists and their effects

A 
•	Opioids, unlike many other peptide systems have some good small-molecule drugs that are agonists or antagonists (morphine, naloxone)
o	Naltrexone
	Alcohol abuse/gambling 
o	Racecadotril (peptidase inhibitors)
	Constipation 
	Used in France, South America and Asia
91
Q

Why are neuropeptide systems important drug targets and how is this approached?

A
  • Drug companies focusing on peptide systems with best small molecule drugs which include CRF, vasopressin, neurotensin and tachykinin
  • Neuropeptides are involved in major brain disorders such as anxiety, depression and schizophrenia but are not great successes in translation to clinical practice
92
Q

What is corticotropin releasing factor and where is it synthesised?

A

• Corticotropin releasing factor (CRF)
o 41 amino acid peptide
o Synthesised in lateral hypothalamus

93
Q

How is corticotropin releasing factor delivered and where is it released?

A

o Release:
 Delivered to portal circulation (acts on pituitary to release corticotropin)
 Released in brainstem, amygdala, BNST, cortex, etc.

94
Q

Describe where the two corticotropin releasing factor receptors are expressed

A

 CRF1-widely expressed in CNS and some expression outside, ligands are CRF and urocortin
• CRF1 on corticotropic cells increase corticotropin release
 CRF2- narrow expression- lateral septum, ligands UNC2 and UNC3

95
Q

What evidence is there on CRF’s effect on depression and anxiety?

A

o CRF and depression and anxiety
 CRF is key in coordinating behavioural and metabolic responses to stress
 Evidence from this comes from a range of experiment including:
• Stress favours development of depression and anxiety
• CRFR1 mutations associated with depression and anxiety
• CRF administration in mice increases behavioural stress
• High stress mice have high CRF levels
• CRFR1 overexpressing mice have higher behavioural stress
• CRFR1 antagonists suppress behavioural changes associated with stress

96
Q

Describe the preclinical
and clinical success of CRFR1 antagonists for anxiety and depression and why there is discrepancy between the two in terms of success.

A

o Almost all drug companies tried to develop and discover CRFR1 antagonists
 Mixture of results from clinical trials but overall not successful
• Could not show drug effect on CRFR1 antagonist
 Animal studies were positive. One of the reasons for this discrepancy between preclinical and clinical may be:
• Poor animal models/tests
o Poor modelling for human anxiety and depression (e.g. forced swim test)
o Animal models validated by current drugs
o Very homogenous populations used
 CRFR1 antagonists might only be useful in humans with population where there might be abberant CRFR1 regulation of stress/anxiety circuits
o May need genetic testing to find right population for CRF effect
o No pet ligands for CRFR1 to allow drug concentration determinations
 Cannot establish receptor occupancy in brain

PCOL3922 (5 decks)

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