Neurotransmitters, receptors and pathways Flashcards
What does this 2S-3R-2D (SSRRRDD) system stand for?
> Synthesis > Storage > Release > Receptors > Reuptake > Degradation > Drugs and Disease
What are the 3 components of a synapse?
> Presynaptic terminal
- synthesis, storage, re-uptake, degradation
> Synaptic cleft
- NT is released
> Postsynaptic region
- ionotropic/metabotropic receptors
What are the characteristics of Glutamate?
> Amino acid > Widely distributed in CNS > Occurs in 70% of all synapses > Very little in the PNS > Ubiquitous excitatory NT in the CNS
How is Glutamate synthesised?
> In glial: α-Oxoglutarate is converted into Glu by GABA Transaminase
In neurons: Glutamine is converted into Glu by Glutaminase
How is Glutamate stored in the presynaptic terminal?
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
How are the Glutamate NTs released in the synaptic cleft?
> 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
What are the Glutamate receptors?
> 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
What is the process of Glutamate reuptake?
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
What is the degradation process of Glutamate?
> 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
What are the drugs related to Glutamate?
> For NMDARs (transferring Na+ and Ca2+)
- Ketamine: dissociative anaesthetic and channel blocker
- Memantine: competitive antagonist
> For AMPAR/kainateR (transferring Na2+)
- Perampanel: competitive antagonist
What are the diseases related to Glutamate?
> Recreational use of drugs (PCP, ketamine etc)
> Epilepsy is associated with the glutamatergic system
- controls brain excitability
> Glu is critical to all CNS functions
What are the characteristics of GABA?
> Amino acid
Widely distributed in the CNS (30% of all synapses)
Very little in the PNS
Ubiquitous inhibitory NT in the CNS
How is GABA synthesised?
Glutamic Acid Decarboxylase (GAD) transforms Glu into GABA
How is GABA stored in the presynatpic terminal?
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
How is GABA released in the synaptic cleft?
Ca2+ dependent vesicular release (like Glu)
- mainly occurs at the axon terminal bouton
What are the GABA receptors?
> Ionotropic receptors
- GABA-A: allow in Cl-
> Metabotropic receptors
- GABA-B coupled to G-proteins Gi and Go
What is the process of GABA reuptake?
> GAT1 - neuronal GABA transporter - takes GABA NT back into presynaptic neuron
> GAT3 - glial GABA transporter - takes GABA NT back into glial cells, particularly astrocytes
What is the GABA degradation process?
By an enzyme: GABA transaminase
- occurs mostly in astrocytes
- ⍺-Oxoglutarate converted to Glu
- GABA converted into succinct semialdehyde
What are the drugs related to GABA-A receptors?
> Clinically useful:
- benzodiazepines
- ethanol
- anaesthetics
- barbiturates: sedative
> Not used clinically:
- Muscimol: agonist activating the receptor
- Bicuculine: competitive antagonist
- Picrotoxin - GABA-A receptor channel blocker
What are the drugs related to GABA-B receptors?
> Baclofen: agonist
> Saclofen: competitive antagonist
> Tiagabine: interferes with re-uptake by blocking GAT (GABA transporter)
> Vigabatrine: blocks GABA transaminase (degradation)
What are the diseases related to GABA?
> Epilepsy
Anxiety
Insomnia
What are the characteristics of dopamine?
> Monoamine
> 4 pathways
- Mesolimbic: VTA to midbrain
- Mesocortical: VTA to PFC
- Nigrostriatal: substantia nigra to midbrain
- Tuberoinfundibular: hypothalamus to brain stem
How is dopamine synthesised?
> Tyrosine (diet) is converted into DOPA by Tyrosine hydrixylase
DOPA is converted into Dopamine by Dopa decarboxylase
How is dopamine stored in the presynaptic terminal?
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
Why are vesicles acidic?
Because they have proton pumps.
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
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)
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)
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
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
What are the diseases related to dopamine?
> Parkinson’s
Schizophrenia
Hormonal disturbances
Drug dependance
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
What are platelets?
Smallest blood cells involved in regulation of hemostass and thrombosis.
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
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
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
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
What is the 5-HT reuptake process?
Transported back into presynaptic terminal by serotonin transporter (SERT)
- co-transported by Cl- and 2Na+
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
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)
What are the disease related to 5-HT?
> Depression
Anxiety
Hallucinations
> 5-HT helps regulates mood, sleep/wake cycle and appetite
