GABA, Glutamate and their receptors Flashcards
what are metabotropic receptors ?
coupled to G protein - open or close ion channels via intermediaries
slower response
transduce signal to the cell interior - indirectly activate ion channels on the plasma membrane through signalling cascade which involved G proteins
what are ionotropic receptors?
ligand gated ion channels
rapid response
depolarise or hyperpolarise the post synaptic cell- depends on receptor type and ionic gradient
what is glutamate ?
most abundant excitatory neurotransmitter in the vertebrae nervous system
what is GABA?
most abundant inhibitory neurotransmitter in the vertebrate nervous system
when glutamate and is present in the synaptic cleft where does it go to be removed ?
enters glial cells or astrocytes or presynaptic terminal
what enzyme converts glutamate to glutamine ?
glutamine synthetase
glutamine can be taken from glial cells into neurons
if too much glutamate is present what can it cause ?
excitotoxicity
it can be highly toxic
a low concentration of glutamate applied to neurons in culture kills the cells
what was discovered in the 1970s about glutamate ?
glutamate given orally produces neurodegeneration in vivo
- this caused considerable alarm because of the widespread use of glutamate as a taste enhancing food additive MSG
what is excitotoxcity associate with ?
activation of NMDA receptors
- results mainly from a sustained rise in intracellular calcium concentration
- there are mechanism that act normally to protect neurones- calcium transport system
what are the glutamate receptors like ?
metabotropic ones - mGluRs 1-8
- slow and modulatory
ionotropic ones
- AMPA, Kainate and NMDA - receptors are named after the agonists that bind to them with high specificity
- fast synaptic transmission
what are the subunits of NMDA receptors ?
NR1
NR2A, B, C and D
NR3A and B
what are the subunits of AMPA receptors?
GluR1
GluR2
GluR3
GluR4
what are the subunits of Kainate receptors ?
GluR5 GluR6 GluR7 KA1 KA2
what are the classes of metabotropic glutamate receptors ?
class1 - mGluR1 and mGluR5 class2- mGluR2 and mGluR3 class 3 - mGluR4, mGluR6, mGluR7 and mGluR8
what effects does activation of class 1 glutamate receptors have ?
stimulates phospholipase c
PIP2 is cleaved into DAG and IP3
they are activated by trans-ACPD and quisqualate
what happens when class 2 glutamate metabotropic receptors are activated ?
inhibit adenylyl cyclase
activated by trans-ACPD and quisqualate
what happens when the class 3 glutamate metabotropic receptors are activated ?
inhibit adenylyl cyclase
activated by L-AP4 and L-SOP
no effect caused by trans-ACPD and quisqualte so they can be differentiated from the class 2 receptors
act ass autoreceptors
what is the obligatory subunit of NMDA receptors ?
NR1
if its not present then the channel cannot function
what binds to the NR1 subunit of NMDA receptors ?
glycine
it doesnt actually activate the channel because it is a co agonist however it causes greater activation when glutamate binds
what is PCP and what does it bind to ?
angel dust
binds to NMDA receptors
what are the rules of assembly of AMPA receptors ?
- homomultimers= 2 or more identical components
- heteromultimers= 2 or more different components
what are the rules of assembly of kainate receptors ?
GluR 5, 6 and 7 are homomultimers
heteromultimers
what are the rules of assembly of NMDA receptors ?
heteromultimers
NR1 must partner 1 or more NR2 subunits
assemble as hetero-tetramers of 2 obligatory NR1 subunits and 2 regionally localissed NR2 subunits
what are the modulatory sites of NMDA receptors ?
glycine binding sites
polyamine antagonist site
Mg 2+ block
channel blocking drugs
what drugs target glutamate receptors ?
ketamine
PCP
AMPAkines
what percentage of synapses does GABA localise to ?
30%
what drugs are GABAa receptors sensitive and insensitive to and what are the effects of its activation ?
sensitive to BICUCULLINE
insensitive to BACLOFEN
activation causes chloride influx to hyperpolarize the cell
what drugs are GABAb receptors sensitive and insensitive to and what are the consequences of its activation ?
sensitive to BACLOFEN
insensitive to BICUCULLINE
modulates neurotransmitter release via potassium ad calcium channels
where is the GABA binding site in GABAa receptors?
between the alpha and beta subunits
where is the benzodiazepine binding site in the GABAa receptors ?
between the alpha and gamma subunits
where is the alpha 1 subunit of GABAa receptors present ?
widely distributed throughout brain
where are the alpha2 subunits of GABAa receptors present ?
mainly present in the hippocampus
where are alpha 3 subunits of GABAa receptors present ?
mostly in the cortex- none in the cerebellum
where are the alpha 4 subunits of the GABAa receptors present ?
some in the hippocampus
low level expression throughout the brain
where are the alpha 5 subunits of the GABAa receptors present ?
present in CA1 and CA3 regions in the hippocampus
where are the alpha 6 subunits of the GABAa receptors present ?
100% in cerebellum - not present anywhere else
what effect does GABA subunit composition have ?
it determines the intrinsic properties of the channel- affinity, kinetics, conductance, allosteric modulation, probability of channel opening, interaction with modulatory proteins and subcellular distribution
what is the typical in vivo subunit composition of GABAa receptors ?
2 alpha, 2 beta and one gamma or delta subunit
