Neurotransmitter Flashcards
What is glutamate
Amino acid, widely distributed in the CNS, very little in the PNS.
Most important excitatory NT in the CNS
What is the glutamate cycle in a neurone
glutamine is taken and glutaminase converts it to glutamate. Transaminase then converts glutamate to alpha-oxoglutarate.
What is the glutamate cycle in a glia
glutamate is made from alpha-oxoglutarate by GABA transaminase. Glutamate is then converted into glutamine by glutamine synthase
Where is glutamate stored
Vesicles (20mM concentration)
How is glutamate transported
Transported in by vesicular glutamate transporter (vGlut), from cytosol into vesicle. Uses protons (2H+) as a concentration gradient. Difference in hydrogen ions is formed from proton pump (uses ATP).
How is glutamate released
Calcium dependent vesicular release - axon end terminal bouton
What are the ionotropic receptors for glutatmate
iGluR (ion channels activated by glutamate)
NMDA cation channel Na+, K+, Ca2+
AMPA cation Channel Na+, K+ (some Ca2+)
Kainate cation channel Na+, K+
Each subunit has 3 transmembrane units and a P loop. Glutamate binds on N terminal. Needs 4 subunits for one receptor.
What are the metabotropic receptors for glutamate
mGluR (G-protein coupled receptors, class C)
Group I - mGLuR1 & mGLuR5 couple to Gq and G11 G proteins
Group II - mGluR2 & mGluR3 couple to Go (most common in the nervous system) and Gi G proteins
Group III - mGluR4 & mGluR6-8 couple to Go and Gi G proteins
7 transmembrane domains. Glutamate binds on N terminus. Intracellular area couples to G proteins.
How does glutamate reuptake occur
Glutamate can bind to receptor
Can disappear in bloodstream
Reuptake by excitatory amino acid transporters (AA) - requires cotransport for Na+, H+ and K+. Can be recycled into vesicles straight away. Or via astrocytes: glutamateíglutamine by glutamine synthase and then transported back into the neurone via glutamine transporters. Glutamine is converted to glutamate by glutaminase.
What are NMDA receptor drugs
ketamine (channel blocker), memantine (competitive antagonist for Alzheimer’, phencyclidine
What are AMPA receptor drugs
perampanel (competitive antagonist for epilepsy)
What is GABA
Amino acid, widely distributed in the CNS, very little in the PNS, most important inhibitory NT in the CNS
How is GABA synthesised
glutamate by GAD (glutamic acid decarboxylase)
Where is GABA stored
Stored in vesicles by vGABAT. Pumped in by hydrogen ions, which is activated by ATP activated proton pump.
How is GABA released
Calcium dependent vesicular release, axon end terminal bouton
What are the ionotropic GABA receptors
GABAa receptor - anion channel Cl-
4 transmembrane units. Needs 5 subunits. Has binding site for benzodiazepines.
What are the metabotropic GABA receptors
GABAb receptor couple to Gi and Go G proteins.
7 transmembrane units.
How is GABA transproted
GAT1: neuronal GABA transporter
GAT3: glial GABA transporter
How does GABA reuptake occur
Alpha-oxoglutarate converted to glutamate by GABA transaminase
GABA converted to succinic semialdehyde by GABA transaminase
This mostly occurs in glia
What are GABAa drugs
muscimol (agonist), bicuculline (competitive antagonist), picrotoxin (channel blocker), benzodiazepines, ethanol and some general anaesthetics are all positive allosteric modulators
What are GABAb drugs
baclofen (agonist), saclofen (competitive antagonist)
Reuptake: tiagabine (blocks GAT)
Degradation: vigabatrine (blocks GABA-t)
What is acetylcholine
Lower motor neurones, GI tract, preganglionic autonomic nerves, post ganglion parasympathetic, retina
Usually long distance neurones or striatal interneurons
How is Ach synthesised
Synthesised from choline and acetyl-CoA with choline acetyltransferase (ChAT). Occurs in the nerve terminal. ChaT synthesised in the cell body and transported to the terminals
How is Ach stored
Stored in vesicles (up to 100 mM, compared to cytosol concentration of 1mM). Exchanged with hydrogen ions with vesicular acetylcholine transporter.
How is Ach released
Calcium dependent vesicular release. End terminal. Vesicular pools: releasable, recycling and reserve
What are nicotinic receptors for Ach
Ligand gated ion channels nicotinic (pentameric):
4 transmembrane domains with 5 subunits to produce functional channel
What are muscarinic receptors for Ach
GPCRs (class A, rhodopsin type), muscarinic:
M1 - Gq/GII
M2 - Go/Gi
M3 - Go/GII
M4 - Go/Gi
M5 - Gq/GII
7 transmembrane domains. Binding for acetylcholine in the transmembrane domain
How does Ach reuptake ocur
Choline transporter for reuptake (Ach must be degraded to choline before it can be reuptaken)
Acetylcholinesterase breaks acetylcholine into choline and acetic acid. Mostly located in the synaptic cleft (extracellular)
What are the drugs for Ach storage
vesamicol (blocks transporter)
What are the drugs for Ach release
Botulinus toxin
What are the drugs for nAch receptor
Full agonists - suxamethonium, nicotine
Partial - varenacline (stops smoking, but does not give withdrawal symptoms)
Reversible antagonist - pancronium, vercuornium
Irreversible antagonist - alpha-bungarotoxin
What are the drugs for mAch receptor
Full agonists - muscarine, oxotremorine M
Partial agonist - McN-A-343
Reversible antagonsits - atropine, ipratropium, benzotropine, procyclidine (CNS active
What are the reuptake drugs for Ach
hemicholinium
What are the degradation drugs for Ach
endophonium, neostigmine, physostigmine, galantamine, rivastigmine
What is dopamine
Monoamine
Location in location (e.g. nigrostriatal pathway, tubero-hypophyseal pathway, mesocortical pathway (overactive in schizophrenia), mesolimbic pathway)
How is dopamine synthesised
Tyrosine->Dopa with tyrosine hydroxylase
Dopa->Dopamine with dopa decarboxylase
How is dopamine stored
Storage with VMAT (vesicular monoamine transporter) - 1 or 2 can be cell type specific. Exchange for 2 hydrogen ions
How is dopamine released
Calcium dependent vesicular release
End terminal
En passant varicosities
What are dopamine receptors
All GPCRs (class A, rhodopsin-like)
DI-like: D1, D5 coupled to Gs
D2-like: D2, D3, D4 coupled to Gi
7 transmembrane domain, with binding inside the transmembrane domain
How does dopamine reuptake occur
dopamine active transporter (DAT), requiring CL- and 2 Na+
How does dopamine degradation occur
output is homovanillic acid (ideally in CSF or urine)
Two main enzymes are MAO and COMT
What are dopamine receptor drugs
Full agonists - DA, apomorphine, bromocriptine
Antagonists - haloperidol, chlorpromazine (anti-schizophrenic)
Reuptake: cocaine, bupropion, methylpenidate (Ritaline)
What are dopamine synthesis drugs
L-dopa
What are dopamine release drugs
amantadine
What are dopamine storage drugs
Reserpine, methamphetamine
What are MAO inhbitiors
phenelzine (anti-depressant), selegiline (MAO-B)
What are COMT inhibitors
entacapone, tolcapone
