Neurotransmitters, receptors and pathways Flashcards

1
Q

What does this 2S-3R-2D (SSRRRDD) system stand for?

A
> Synthesis
> Storage
> Release
> Receptors
> Reuptake
> Degradation
> Drugs and Disease
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2
Q

What are the 3 components of a synapse?

A

> Presynaptic terminal
- synthesis, storage, re-uptake, degradation

> Synaptic cleft
- NT is released

> Postsynaptic region
- ionotropic/metabotropic receptors

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3
Q

What are the characteristics of Glutamate?

A
> Amino acid
> Widely distributed in CNS
> Occurs in 70% of all synapses
> Very little in the PNS
> Ubiquitous excitatory NT in the CNS
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4
Q

How is Glutamate synthesised?

A

> In glial: α-Oxoglutarate is converted into Glu by GABA Transaminase
In neurons: Glutamine is converted into Glu by Glutaminase

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5
Q

How is Glutamate stored in the presynaptic terminal?

A

Glu is transported by 3 vesicular glutamate transporters (vGluT) into vesicles

  • vGluT1
  • vGluT2
  • vGluT3

> vGluT brings Glu into the vesicle

  • for Glu to get in: H+ ions are pumped out
  • > high concentration of Glu in the vesicle
  • H+ is brought in the vesicle by a proton pump which converts ATP-ADP energy into high concentration of H+ which can be exchanged for Glu NT
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6
Q

How are the Glutamate NTs released in the synaptic cleft?

A

> Glu NTs are released by the nerve terminal at the axon terminal bouton

> Ca2+ dependent process: provokes exocytosis of vesicle content
- Ca2+ required to move and fuse vesicles with the membrane to allow NTs into synaptic cleft

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7
Q

What are the Glutamate receptors?

A

> Ionotropic receptors iGluR: ion channels activated by Glu

  • NMDA: allow in Na+ / Ca2+ (significantly)
  • AMPA/kainate: allow in Na+
  • these let out a bit of K+

> Metabotropic receptors mGluR: G-protein coupled receptors, class C

  • Group 1: mGluR1 and mGluR5
  • Group 2: mGluR2 and mGluR3
  • Group 3: mGluR4 and mGluR6-8
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8
Q

What is the process of Glutamate reuptake?

A

Excitatory Amino Acid Transporter (EAAT) regulate this recycling process into the presynaptic neuron or glial cell (e.g. astrocyte)

> EAAT takes Glu back into presynaptic terminal, where its recycled into vesicles and reused
or
EAAT takes Glu into the astrocyte, where its converted into glutamine by glutamine synthase
- Glu can be transported out of the astrocyte by a glutamine transporter (GlnT) back into the presynaptic terminal
- once into the presynaptic terminal: glutamine is again synthesised into Glu by glutaminase

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9
Q

What is the degradation process of Glutamate?

A

> Glu is quickly removed from synaptic cleft by EAAT into presynaptic neurons for recycling, or into astrocytes

> In astrocytes Glu is converted to glutamine by glutamine synthase

> Glutamine is transferred to the presynaptic neuron where it is converted back to Glu by glutaminase to be reused

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10
Q

What are the drugs related to Glutamate?

A

> For NMDARs (transferring Na+ and Ca2+)

  • Ketamine: dissociative anaesthetic and channel blocker
  • Memantine: competitive antagonist

> For AMPAR/kainateR (transferring Na2+)
- Perampanel: competitive antagonist

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11
Q

What are the diseases related to Glutamate?

A

> Recreational use of drugs (PCP, ketamine etc)

> Epilepsy is associated with the glutamatergic system
- controls brain excitability

> Glu is critical to all CNS functions

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12
Q

What are the characteristics of GABA?

A

> Amino acid
Widely distributed in the CNS (30% of all synapses)
Very little in the PNS
Ubiquitous inhibitory NT in the CNS

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13
Q

How is GABA synthesised?

A

Glutamic Acid Decarboxylase (GAD) transforms Glu into GABA

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14
Q

How is GABA stored in the presynatpic terminal?

A

Vesicular storage by vesicular GABA transporter (vGABAT)

> vGABAT brings GABA in the vesicle

  • H+ ions are pumped out for GABA to get in
  • H+ is brought in the vesicle by a proton pump which converts ATP-ADP energy into high concentration of H+ which can be exchanged for GABA NT
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15
Q

How is GABA released in the synaptic cleft?

A

Ca2+ dependent vesicular release (like Glu)

- mainly occurs at the axon terminal bouton

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16
Q

What are the GABA receptors?

A

> Ionotropic receptors
- GABA-A: allow in Cl-

> Metabotropic receptors
- GABA-B coupled to G-proteins Gi and Go

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17
Q

What is the process of GABA reuptake?

A

> GAT1 - neuronal GABA transporter - takes GABA NT back into presynaptic neuron

> GAT3 - glial GABA transporter - takes GABA NT back into glial cells, particularly astrocytes

18
Q

What is the GABA degradation process?

A

By an enzyme: GABA transaminase

  • occurs mostly in astrocytes
  • ⍺-Oxoglutarate converted to Glu
  • GABA converted into succinct semialdehyde
19
Q

What are the drugs related to GABA-A receptors?

A

> Clinically useful:

  • benzodiazepines
  • ethanol
  • anaesthetics
  • barbiturates: sedative

> Not used clinically:

  • Muscimol: agonist activating the receptor
  • Bicuculine: competitive antagonist
  • Picrotoxin - GABA-A receptor channel blocker
20
Q

What are the drugs related to GABA-B receptors?

A

> Baclofen: agonist

> Saclofen: competitive antagonist

> Tiagabine: interferes with re-uptake by blocking GAT (GABA transporter)

> Vigabatrine: blocks GABA transaminase (degradation)

21
Q

What are the diseases related to GABA?

A

> Epilepsy
Anxiety
Insomnia

22
Q

What are the characteristics of dopamine?

A

> Monoamine

> 4 pathways

  • Mesolimbic: VTA to midbrain
  • Mesocortical: VTA to PFC
  • Nigrostriatal: substantia nigra to midbrain
  • Tuberoinfundibular: hypothalamus to brain stem
23
Q

How is dopamine synthesised?

A

> Tyrosine (diet) is converted into DOPA by Tyrosine hydrixylase
DOPA is converted into Dopamine by Dopa decarboxylase

24
Q

How is dopamine stored in the presynaptic terminal?

A

Vesicular storage by vesicular monoamine transporter (VMAT)

> VMAT1 or VTMAT2 (cell type specific) brings dopamine into vesicle

  • H+ ions are pumped out for DA to get in
  • H+ is brought in the vesicle by a proton pump which converts ATP-ADP energy into high concentration of H+ which can be exchanged for DA NT
25
Why are vesicles acidic?
Because they have proton pumps.
26
What is the process of dopamine release
> Ca2+ dependent vesicular release - mainly occurs at the axon terminal bouton or > 'en passant' manner: - small release sites located along the axon - dopamine can be released at all these points
27
What are the dopamine receptors?
Metabotropic receptors - all G-protein coupled, class A - D1 and D5 coupled to Gs - D2, D3 and D4 coupled to Go/Gi No ligand-gated ion channels (no ionotropic receptors)
28
What is the dopamine reuptake process?
DA transported back into presynaptic neuron by dopamine active transporter (DAT) AND co-transported by Cl- and 2Na+ (1 chloride ion and 2 sodium ions)
29
What is the dopamine degradation process?
> Several biochemical pathways that lead to the breakdown of DA > Monamine oxydase (MAO) and COMT (catechol-O-methytransferase) convert dopamine into Homovanillic acid
30
What are the drugs related to dopamine?
> DA synthesis - Levodopa: precursor of DA -> increase of DA ; for Parkinson's disease > DA storage: - Reserpine and Methamphetamine block VMAT > DA release: - Amantadine > DA receptors: - full agonist: DA itself, apomorphine, bromocriptine - competitive antagonists: haloperidol, chlorpromazine > DA reuptake: - cocaine, bupropion, methylphenidate (Ritalin) > DA degradation: - MAO inhibitors: phenelzineu, selegine (MAO-B) - COMT inhibitors: entacapone, tolcapone - both adjacents with L-Dopa - can be used for Parkinson's
31
What are the diseases related to dopamine?
> Parkinson's > Schizophrenia > Hormonal disturbances > Drug dependance
32
What are the characteristics of 5-HT?
> Also called serotonin > Monoamine > Present in enteric nervous system (gastrointestinal control - part of the PNS) at 80% > 5-HT platelet system
33
What are platelets?
Smallest blood cells involved in regulation of hemostass and thrombosis.
34
How is 5-HT synthesised?
> Tryptophan (diet) is converted into 5-hydroxytryptophan by Tryptophan hydroxylase > 5-hydroxytryptophan is converted into 5-hydroxytryptamine (5-HT) by Dopa decarboxylase
35
How is 5-HT stored in the presynaptic terminal?
Vesicular storage by vesicular monoamine transporter (VMAT) > VMAT1 or VTMAT2 (cell type specific) brings 5-HT into vesicle while ejecting H+ ions - H+ is brought in the vesicle by a proton pump which converts ATP-ADP energy into high concentration of H+ which can be exchanged for 5-HT NT
36
What is the 5-HT release process?
> Ca2+ dependent release - mainly occurs at the axon terminal bouton > 5-HT is co-released with neuropeptides - e.g. somatostatin or substance P
37
What are the 5-HT receptors?
> Ionotropic receptor: 5-HT_3 - only 5-HT ligand-gated ion channel - mixed cation channel: allows Na+ and Ca2+ into cell and K+ out > Metabotropic receptors: G-protein coupled - presynaptic: 5-HT1A, 1B, 1D, 1E, 1F - postsynaptic: 5-HT2A, 2C
38
What is the 5-HT reuptake process?
Transported back into presynaptic terminal by serotonin transporter (SERT) - co-transported by Cl- and 2Na+
39
What is the 5-HT degradation process?
> 5-HT(hydroxytryptamine) is broken down by MAO into 5-hydroxyindolealdehyde > 5-hydroxyindoleadehyde is broken down by Aldehyde hydrogenase into 5-HIAA(hydroxyindoleacetic acid) - common metabolite that monitors 5-HT
40
What are the drugs related to 5-HT?
> 5-HT synthesis: - p-chloropenylalanine (TH inhibitor) - L-trytophan (precursor): used in depression > 5-HT storage: tetrabenazine > 5-HT release: MDMA > 5-HT receptors: - full agonist: 5-HT itself, sumatriptan (5-HT1D) used for migrains - partial agonist: buspirone (5-HT1A) - competitive antagonists: ondansetron (5-HT3), ketanserin (5-HT2A) > 5-HT reuptake: - SSRIs: e.g. citalopram - TCAs: e.g. imipramine - amphetamine (MDMA) > 5-HT degradation: - MAOI (phenelzine)
41
What are the disease related to 5-HT?
> Depression > Anxiety > Hallucinations > 5-HT helps regulates mood, sleep/wake cycle and appetite