GABA receptors Flashcards
What enzyme converts glutomate to GABA?
GAD or Glutomate decarboxylase
what is the product of GABA trasaminase?
succinate semialdehyde
what enzyme converts GABA to succinate semialdehyde?
GABA-T or
GABA transaminase
what enzyme converts succinate semialdehyde to succinate?
SSDH
what can succinate be used for?
it can be used in KREB cycle
what are the 2 enzyme that help us to get rid of GABA?
GABAT and SSDH
what is the drug that can block both GABA-T and SSDH and also facilitate the production of GAD?
Valproate
what is Valporate used for clinically?
used as a AED for epileptic patient
what are the 2 different familly of GABA transporter?
GAT and VGAT
how many different GAT do we Have?
3, GAT1, GAT2, GAT3
what drug can block all family of GABA transporter?
Nipecotate
what are the 2 blocker for VGAT familly?
Nipecotate
Vigabatrin (selective blocker fot VGAT)
where in the body can you find GAT1 and GAT3?
neuronal, glial
where in the body can you find GAT 2?
pia, arachnoid – membrane surrounding the brain
where in the body can you find VGAT?
(vesicular GABA transporter) responsible for packaging NT
where does most of the metabolism of GABA occure?
in glial cell and some in neuron
what taype of GABA receptors is almost exclusively post synaptically?
GABA-A
where would you find GABA-B, pre or post synaptically?
both, pre and postsynaptically
where would you find VGAT in a cell?
located on vesicular membrane
where are the GAT familly of GABA transporter located in a synapse?
located presynaptic terminal or on glial membrane
why is Valporate one of the best epileptic drug?
because it strongly facilitates CNS inhibition
how does Valporate enhance GABAergic transmission?
1-Facilitates GAD activity by GABA production from Glutamate
2-Blocks inhibition of GABA or block the breakdown of GABA by blocking GABA-T and SSDH
•Where is GABA produced, in neuron of Glial cell?
in neuron (remember we dont have inhibitory Glial cell)
how many tyoe of GABA receptor do we have? how are they expressed?
GABAb1 and GABAb2
they are coexpressed, they both have to be present as a heterodimers inorder to have a functional GABA receptor
how many transmembrane segment makes up a GABA receptor?
7
what happens if a neuron only expresses GABAb1?
they will not even show up in the cell membrane, they are manufactured but they will never make it any farther out of the cell than the ER. There is nothing for GABA to bind to
what if we have a neuron that expressed only in the second type of protein, GABAb2?
they will get transported form ER and expressed at the cell membrane but we still don’t have a place for a functional receptor
why GABAb1 and GABAb2 both have to be present to have a functional receptor?
becaue the GABAbr1 provide the binding site for G-protein and the GABAb2 provides the binding site for GABA
_double check this question _
whta does obligate heterodimers means?
meaning it only works if we have both present, that what obligate means
what kind of G-protein can binds to GABAb receptors?
Gi and Go type of G-protein can bind to them
how does Gi alpha subunit decrease the activity of PKA?
The Gi alpha subunit will inhibit the AC and will decrease the activity of PKA because PKA depends on the product of AC
why the Go mediated effect of GABAb receptor is not mediated by the alpha subunit?
The alpha subunit is diffusible but beta-Gamma subunits have to stay membrane bound. But they can act upon thing that are also membrane bound, foe example they act upon VDCCS and VDKC.
what is the effect of Beta-gamma subunit of Go on VDCCs and VDKCs?
Beta-gamma subunit of Go inhibits VDCCs and activate VDKCs
what is the drug that can block G-protein though its alpha subunit?
PTX (pertussis toxin)
what are the GABA agonist ?
- GABA (endogenous) agonist
- Baclofen (marketed as an antispasmodic) very potent agonist
what are the GABA antagonist?
- Phaclofen (competitive antagonist)
- Saclofen (competitive antagonist)
what are the Effects of divalent cations on GABAb Receptors? (the reason they are called GABA modulator)
Many of the divalent cations change the affinity for binding of GABA to the receptor
what are some of the divalent cations that can enhance GABA binding?
Mg2+ (stronger than Ca2+)
Ca2+
what are some of the divalent cation that can inhibit GABA binding?
Hg2+ (stronger than Pb)
Pb2+
what is the effect of GABA on post synaptic Ca2+ current?
they decrease the amount of Ca2+ that comes in to post synaptic cell.
if we apply Baclofen, a GABAB agonist, we can strongly reduce the amount of Ca2+ influx. but it is reversable
what kind of channels are P-type channel?
- High voltage activated Ca2+ channel
- They are largely responsible presynaptically for release of neurotransmitter.
Baclofen or GABA has important role in determining how much neurotransmitter will be released acting upon presynaptic membrane. what type of Ca2+ channel does baclofen block?
P/Q/R
what kind of channel does nimodipine block?
blocks L type Ca2+ channel
what kind of Ca2+ channel does ω-conotoxin G6A block?
blocks N type Ca2+ channel
what kind of Ca2+ channel does CTX and flunarizine block?
blocks T type channel
how could we prove that baclofen has blocked on P/Q receptor?
we would apply a different drug such as ω-agatoxin wich blockes the Ca2+ current and then measure the current on P/Q current. then apply baclofen and measure the curent again, we see no difference.
name four drugs that can block all type of Ca channel (P, L, T, N) when they are combined?
Nimodipine + CTX + flunarizine + agatoxin (or baclofen)
GABAb receptor blocks VDCCs via what kind of G-protein subunit?
via Go beta-gamma subunits
since we know that blocking of VDCC with GABAb receptors is a G-protein mediated effect, what phosphorylated molecule is require for G-protein mediated receptor coupled event?
GTP, If there is no GTP, baclofen will have no effect and will not block the presynaptic Ca2+ current.
what is the effect of pertussis toxin on the effect of baclofen?
• If we apply pertussis toxin (bound to G-proteins) and blocks G-protein, baclofen will have no effect
what happens when we apply GABA agonist to GABAergic synapse?
the Release of GABA then inhibit cell, the next time you fire there is a smaller IPSP because you have blocked some of the Ca channels presynaptically through beta-gamma Go mediated mechanism
1- Less Ca influx, less likelihood of fusion of vesicles
2- Less GABA is released
3- Less IPSP postsynaptically
what do we call a GABAb Receptor on a presynaptic GABAergic neuron terminal?
autoreceptors,
it block the release of GABA and other neurotransmitter release
what happens when GABA was applied to postsynaptic cell what kind of current did they exhibited?
very long lasting IPSC
IPSC that are mediated by GABAa receptors are very brief
What type of IPSC would GABAa produce?
it would be shorth and inward current
when does GIRK gets actvated?
it is activated when a molecule of GABA binds to dimeric GABAb receptors and that thoes reseptors are been strongly phosphorylated
