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: Release of NT
- 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 presence in the PNS
- Ubiquitous excitatory NT in the CNS
How is Glutamate synthesised?
Glutamate (SSRRRDD: Synthesis)
- In glial cells: 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?
Glutamate (SSRRRDD: Storage)
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 -> ensuring 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?
Glutamate (SSRRRDD: Release)
> 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?
Glutamate (SSRRRDD: 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?
Glutamate (SSRRRDD: 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?
Glutamate (SSRRRDD: Degradation)
Glu is quickly removed from synaptic cleft by EAAT (Excitatory Amino Acid Transporter) 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?
Glutamate (SSRRRDD: Drugs & Diseases)
> 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?
Glutamate (SSRRRDD: Drugs & Diseases)
- 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?
GABA (SSRRRDD: Synthesis)
- Glutamate -> Glutamic Acid Decarboxylase (GAD) -> GABA
How is GABA stored in the presynatpic terminal?
GABA (SSRRRDD: Storage)
- 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?
GABA (SSRRRDD: Release)
Ca2+ dependent vesicular release (like Glu) and mainly occurs at the axon terminal bouton
What are the GABA receptors?
GABA (SSRRRDD: Receptors)
- Ionotropic receptors
- GABA-A: allows in Cl-
- Metabotropic receptors
- GABA-B coupled to G-proteins Gi and Go
What is the process of GABA reuptake?
GABA (SSRRRDD: 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?
GABA (SSRRRDD: Degragation)
By an enzyme: GABA transaminase
- occurs mostly in glial cells (e.g. astrocytes)
- ⍺-Oxoglutarate converted to Glutamate; GABA converted into succinct semialdehyde
What are the drugs related to GABA-A receptors?
GABA (SSRRRDD: Drugs & Diseases)
GABA-A (Ionotropic 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?
GABA (SSRRRDD: Drugs & Diseases)
GABA-D (Metabotropic 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?
GABA (SSRRRDD: Drugs & Diseases)
- Epilepsy
- Anxiety
- Insomnia
are all associated with GABA
GABA’s major function in the CNS associated with the brain inhibitory actions
What are the characteristics of dopamine?
- Monoamine, located in a specific areas of the CNS
- 4 pathways
- Mesolimbic (associated with Schizophrenia): VTA (ventral tegmental area) to midbrain
- Mesocortical: VTA to PFC
- Nigrostriatal pathway (associated with Parkinson’s): substantia nigra to midbrain
- Tuberoinfundibular: hypothalamus to brain stem
How is dopamine synthesised?
Dopamine (SSRRRDD: Synthesis)
- 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?
Dopamine (SSRRRDD: Storage)
- 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?
Dopamine (SSRRRDD: 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?
Dopamine (SSRRRDD: Receptors)
Only 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?
Dopamine (SSRRRDD: Reuptake)
- 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?
Dopamine (SSRRRDD: Degradation)
- 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?
Dopamine (SSRRRDD: Drugs & Diseases)
- 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? c
Dopamine (SSRRRDD: Drugs & Diseases)
- Parkinson’s, Schizophrenia, Hormonal disturbances, Drug dependance
- Dopamine is involved in motor control and pituitary control, and may be involved in reward system and thoughts
What are the characteristics of 5-HT?
- 5-HT is 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 hemostasis and thrombosis.
How is 5-HT synthesised?
5-HT (SSRRRDD: Synthesis)
- 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?
5-HT (SSRRRDD: Storage)
- 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?
5-HT (SSRRRDD: Release)
- 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?
5-HT (SSRRRDD: Receptors)
- Ionotropic receptor: 5-HT_3
- the 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?
5-HT (SSRRRDD: Reuptake)
Transported back into presynaptic terminal by serotonin transporter (SERT)
- co-transported by Cl- and 2Na+
What is the 5-HT degradation process?
5-HT (SSRRRDD: Degradation)
- 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 (SSRRRDD: Drug & Diseases)
- 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 migraines
- 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
