Barbiturate/Diazepam - GABA signalling Flashcards
volume tranmission
intercellular communication –> occurs in CSF, movement via diffusion
slow transmission
e.g. dopamine
GABAergic neurons
release GABA
does GABA or glutamate have a chiral carbon
Glu
GAD
glutamate decarboxylase
role of glutamate decarboxylase
catalyses decarboxylation of glutamate to GABA
2 forms of GAD
GAD65
GAD67
where is GAD65 found
nerve terminals
where is GAD 67 found
throughout cells
GABA biosynthesis
GABA is made from glutamate
transporters to get GABA into cells
GAT1
GAT3
transporters to get GABA into vesicles
VGAT
other use of VGAT
also puts Glycine into vesicles
receptors activated by GABA
GABA A and GABA B receptors
termination of GABA neurotransmitter action
diffusion
uptake by VGAT transporters
ionotropic GABA receptor
GABA A
metabotropic GABA R
GABA B
properties of GABA A R
ionotropic pentameric cys loop on extracellular side N and C terminals both extracellular Cl- through central pore
most common GABA A R structure
a1 B2 a1 y2 B2
properties of GABA B R
metabotropic
7 TM domain
obligate dimer
N-terminus extracellular/C-terminus intracellular
linked to K+ channels via G-proteins
GABA C
sub class of GABA A receptors therefore also ionotropic however insensitive to GABA A antagonist bicucilline less sensitive to GABAzine
GABAzine
competitive antagonist
ligands binding to orthosteric site
bind to GABA site
muscimol
GABA agonist
psychoactive substance in mushrooms
GABA competitive antagonists
bicucilline
GABAzine
picrotoxin
non-competitive antagonist
pore blocker of GABA
allosteric ligands
bind to a site alternative to GABA site
modulate signalling
examples of GABA allosteric modulators
benzodiazepines
alcohol
neurosteroids
barbiturates
benzodiazepine site
between gamma and alpha 1 subunits
effect of BDZ on GABA R
postivie allosteric modulator
increases effect of GABA
increases frequency of bursts of channel opening
physiological effects of BDZ
reduce anxiety
anticonvulsant
promote sleep
can be addictive
effect of inverse agonists at GABA site
decreases effect of GABA
therfore seizures might be promoted
competitive antagonist at BDZ-site
flumanezil
property of BDZ-site ligands that makes them good for focussed therapeutic use
some of the ligands have different affinities and selectivity for GABA A receptor subtypes
e.g. BDZ doesnt work on a6 subunits
why can barbiturates/neurosteroids kill you at high dose
they directly activate receptors and cause respiratory failure
effects of barbiturates
bind to different site to BDZ
increase duration of bursts of channel opening
positive allosteric modulator
where do GABA A receptors clsuter
on the post synaptic membrane
what causes GABA A R to cluster
intracellular proteins
therapeutic uses of short/intermediate-acting barbiturates
sleeping pills
sedatives
which GABA reeceptor has a slow IPSP and why
GABA B receptor
mediated by GIRK channels and K+ movement
GIRK stands for
G-protein coupled Inwardly Rectifying K+ channel
mechanism of baclofen to create an IPSP
hyperpolarises post-synaptic cells by increasing K+
how does baclofen decrease neurotransmitter release from pre-synaptic
inhibits Ca2+ channels
how does baclofen decrease cAMP production
inihbiits adenyl cyclase
main function of baclofen
selective agonist of GABA B receptors
acts like Gi/o –> decreased cAMP and activates GIRK channels
“plus side” of GABA A receptor
formed by TM2 and TM3 of the principal (upper) subunit
‘minus side’ of GABA A receptor
formed by parts of TM1 and TM2 of the complementary subunit
4 transmembrane domains of GABA A make up which two subunits
principal subunit
complementary subunit
does the IPSP change size with successive action potentials
if 2 identical presynaptic stimuli are given in rapid succession, the 2nd IPSP will be smaller
