neurotransmitters Flashcards
what is glutamate
an amino acid that can be synthesised in all cells - metabolic glutamate and transmissible glutamate
how is glutamate synthesised
from glucose via TCA and GABA-T in krebs cycle
from glutamine by glutaminase
how is glutamate processed and released from cells
- glutamate made in neuron
- loaded into synaptic vesicle via V-GLUT
- on Ca2+ influx, synaptic vesicle releases glutamate into synapse
- glutamate is taken up into astrocyte or neuron via EAAT
what are the two types of glutamate receptors
metabotropic glutamate receptors - mGluRs - GPCR
ionotropic glutamate receptors - ligand gated ion channels
what are mGluRs
GPCRs belonging to C class with large extracellular N-terminal where glutamate binds
8 subtypes mGluR1-8 split into three groups
what are the three mGluR groups
group 1 - mGluR1 and 5
- post synaptic and excitatory
- G alpha Q/11 - increases calcium
group 2/3 - mGluR 2/3 (2) mGluR 4-7 (3)
- presynaptic neuromodulation inhibitors
- G alpha i/o - decreases cAMP
what are the three classes of ionotropic glutamate receptors
NMDA
AMPA
Kainite
- all respond to different synthetic glutamate analogues
- all have similar structures - tetramers
what are NMDAR
- receptors that only respond to Lglutamate and NMDA
- tetrameric that forms a hetero-tetramer of 7 potential subunits
- usually 2GluN1 and 2GluN2
- receptor composition affects properties of receptor
- selective for Na, Ca, K
what are the 5 binding sites present on NMDAR
- glutamate - agonist site
- glycine
- polyamine
- Mg2+
- channel blocking site
how does glutamate bind to NMDAR
each tetramer binds to two molecules of glutamate, requires co-agonist of 2 glycine (D-serine or D-alanine) at GluN1
what competitive agonists can act at the glutamate site on NMDAR
D-AP5
what antagonists can bind to the glycine site on NMDAR
kynurenic acid and CGP 61594
what is the polyamine site on NMDAR
modulator site at amino terminal domain - allosteric modulators - can increase responses
what is the Mg2+ side on NMDAR
Channel is blocked by Mg 2+ at resting neuronal membrane potentials giving NMDAR voltage dependant channel block
what is the channel blocking site on NMDAR
allows for binding when the channel is open - ketamine, memantine
what are AMPAR
ligand gated ion channels that only respond to AMPA and L glutamine - forms a homotetramer or mixed heterotetrametric - impermeable to calcium and mediates fast excitatory transmission
what are KAINITER
ligand gated ion channels that only respond to kainite and L glutamine - structurally similar to AMPAR
what is end plate potential (EPP)
EPP is very large and activates an action potential in the muscle cell which then propagates - type of EPSP
what is EPSP
excitatory post synaptic potential
where are EPSPs formed in the CNS
pre-synaptic neurons - input from many presynaptic neurons is required to generate an action potential - Depolarisation eventually reaches threshold for firing
what are glutamergic receptors
excitatory receptors with round synaptic vesicles and large postsynaptic density
what are GABA receptors
inhibitory receptors with flattened synaptic vesicles with less postsynaptic density
what is post synaptic density
Receptors are clustered by lots of regulatory proteins into areas called a postsynaptic density - usually containing AMPAR (fast) and NMDAR (slow)
which protein is responsible for clustering receptors
PSD-95 - contains PDZ for protein-protein binding - binds directly to NMDAR but binds to TARP to regulate AMPAR
what is synaptic plasticity
long term changes in connectivity between neurons - Long term potentiation (LTP) is a form of synaptic plasticity
what is long term potentiation
- Postsynaptic AMPA receptors are activated but NMDAR requires a sustained depolarisation to relieve Mg2+ block
- Ca2+ entry can activate other enzymes including kinases (PKC, CaMKII) which phosphorylate AMPAR increasing responses
- Phosphorylation increases AMPAR conductance and can increase expression
what is excitotoxicity
High calcium permeability of NMDAR can cause problems - lots of glutamate = lots of calcium = neuronal cell death
what is GABA
main inhibitory neurotransmitter in the brain - widespread and ubiquitous
how is GABA synthesised
precursor is glucose - formed from glutamate by GAD
how is GABA metabolised
by GABA-T
how is GABA stored
synthesis in GABA-ergic nerve terminals and packaged into vesicles and recycled from synapse by GAT or astrocytes via GAT3
what is a drug example of a GABA reuptake inhibitor
guvacine
what are the two types of GABA receptors
ionotropic ligand gated channels
metabotropic receptors
what are ionotropic ligand gated channels
GABAa - post synaptic receptor to mediate fast inhibition via Cl- (influx causes hyperpolarisation and reduces excitability)
what are the 5 drug binding sites on GABAa
receptor site GABA
benzodiazepine site
modulatory site - barbituates
neurosteroid site
pirotoxin site - channel blocking
what is the receptor site on GABAa
agonist site, opens ion channel, 2 sites per pentamer
what is the benzodiazepine site on GABAa
selectively enhances the effects of GABA - at alpha gamma subunit interface
what is the modulatory site on GABAa
increases ligand binding to benzo and receptor site to give stronger response - barbiturates
what is the Neurosteroid site on GABAa
endogenous modulators that enhance effects of GABA
what is the pirotoxin site on GABAa
within the ion channel pore and requires opening - no use- convulsions
what is a GABA metabotropic receptor
GABAb - couples through g alpha i/o - inhibits calcium voltage channels and reduces neurotransmitter release from presynaptic terminals
what is glycine
inhibitory neurotransmitter in the CNS - co-agonist at NMDA, glycine receptor is similar to GABAa
what is the role of 5-HT
CNS neurotransmitter, found in the gut and involved in platelet aggregation
how is 5-HT synthesised
tryptophan hydroxylated by tryptophan hydroxylase to 5-Hhydroxytryptopan - dopa decarboxylase to 5-HT
storage and transport of 5-HT
VMAT loads into vesicles
MAO controls degradation
SERT permits reuptake of 5HT
functions of 5HT
stored and released from serotonergic neurons, similar distribution to noradrenergic neurons - sleep, appetite, mood, pain and thermoregulation
what are the 2 types of 5HT receptors
13 GPCR
1 ligand gated ion channel
what are the 7 names of the 5-HT receptors
5HT3 - ion channel
5HT1A-E - G apla i/o
5HT2A-C - G alpha q/qq
5HT4-7- G alpha S
what are 5HT1B/D agonists used for
triptans - migraines
what are 5HT1A partial agonists used for
buspirone - anxiety
what are 5HT2 antagonists used for
migraine prophylaxis - pizotifen
what are 5HT3 antagonists used for
ondansetron - antiemetic
