Exam 2 Chapter - GABA

Describe the synthesize of GABA and include all precursers and everything.

glutamate ------(glutamic acid decarboxylase/GAD)----→ GABA

Describe GABA:

* major inhibitory amino acid transmitter
* only made in GABAergic neurons
* has an important role in regulating excitability

what does **Allylglycine** do?

* drug
* blocks GABA synthesis
* only used in vitro studies

what does **thiosemicarbazide** do?

* drug
* blocks GABA synthesis
* only used in vitro studies

what does **3-mercaptoprpionic acid** do?

* drug
* blocks GABA synthesis
* only used in vitro studies

what helps move GABA into vesicles?

VGAT

* vesicular GABA transporters
* they can also move glycine into vesicle

what is another name for VGAT

VIAAT

* vesicular inhibitory amino acid transporters

what helps remove GABA from the synaptic cleft?

* GAT-1
* GAT-2
* GAT-3

where do we find GAT-1 and GAT-2?

neurons and astrocytes

Where do we find GAT-3?

only in astrocytes

what does **Tiagabine** do?

* drug
* selective inhibitor for GAT-1
* increases extracellular GABA and enhances GABAergic transmission in several brain areas

How is tiagabine marketed and what is it used for?

* Gabitril
* treats epilepsy

What can GABA be metabolized to? By what enzyme?

* metabolized to: glutamate and succinate
* GABA-T = GABA aminotransferase
* this happens in neurons and astrocytes

Draw the GABA cycle

After neurons release GABA, it can be transported back into the nerve terminal by GAT-1 or transported into nearby astrocytes by GAT-2 or GAT-3. Inside the cell, GABA is metabolized to glutamate and succinate by GABA aminotransferase (GABA-T). In the case of astrocytes, the glutamate is converted into glutamine by the enzyme glutamine synthetase. The glutamine can later be released by the astrocytes, taken up by neurons, converted back into glutamate by the enzyme glutaminase, and finally used to resynthesize GABA.

GABA is also co-released with other NT, which ones?

* glycine
* ACh
* DA
* glutamate

why might some neurons want to release glutamate (excitatory) and GABA (inhibitory) at the same time?

allows for fine tuning of the postsynaptic response

which cells release ACh and GABA at the same time?

basal forebrain cholinergic neurons which give projections to the hippocampus

which cells release DA and GABA at the same time?

Midbrain dopaminergic neurons can accumulate GABA either through GAT-1-mediated uptake or from 4-amino-butanal by an usual biosynthetic pathway. DA and GABA are taken up into the same synaptic vesicles by VMAT2.

which cells release GLutamate and GABA at the same time?

Neurons of the entopeduncular nucleus that project to the lateral habenula synthesize both glutamate and GABA, and the two transmitters are taken up into the same synaptic vesicles by their respective vesicular transporters, VGLUT2 and VGAT.

A neuron that co-releases GABA and glycine would contain which of these chemicals?

a. VGAT

b. VMAT

c. VGAT + VGLUT2

d. VGLUT2 + VAChT

a.

some GABAergic neurons are _____1_____,__ while others are _____2___

1. interneurons
2. projection neurons

what are some areas that are rich in GABA?

1. Cortex and hippocampus = here they are interneurons
2. Striatum and cerebellar purkinje cells = here they are projection neurons

what are spinocerebellar ataxias?

* rare genetic mutations that cuase degeneration and death of Purkinje cells
* causes ataxia, impaired balance and poor motor coordination

describe GABA_A receptor:

* ionotropic
* 5 subunits
* 2 alpha, two betas and one gamma
* they allow CL- to move in to the cell
* causes hyperpolarization and inhibition of the postsynaptic cell

describe GABA_B receptors

* metabotropic

The acion of GABA are primarily mediated by __________ receptors

GABA_A

what does Muscimol do?

* drug
* GABA_A agonist from the mushroom Amanita muscaria

what does Bicuculline do?

* drug
* competitive antagonist for GABA_A receptors
* blocks GABA binding
* if take systematically, can cause convulsions

what does pentylenetetrazol (metrazol) do

* drug
* convulsant drug
* inhibits GABA_A function
* noncompetative antagonist = act at sites distinct from the GABA binding site

what does pocrotoxin do?

* drug
* convulsant drug
* inhibits GABA_A function
* noncompetative antagonist = act at sites distinct from the GABA binding site

GABA_A receptors are sensitive to CNS-depressant drugs such as: _______. What do they do?

* benzodiazepines
* barbituates
* ethanol
* act as positive allosteric modulators - they enhance tha action of GABA on the receptor

what are some other positive modulators for GABA_A receptors

* anasthetics such as propofol (Diprivan)
* Neurosteroids

Which of the following is a positive allosteric modulator of the GABAA receptor?

a.Bicuculline

b.Muscimol

c. BDZ

c

BDZs and ethanol can only _____________, regardless of dose

modulate receptor activity

high doses of barbiturates, anesthetics, and neurosteroids can open the receptor channel even in _____________

the absence of GABA

what does Diazepam (Valium) do?

* drug
* Benzodiazepine
* increases the effect of GABA on a receptor which means that the drug alone without GABA has no effect
* positive allosteric modulator

**Inverse agonists** at the BDZ receptor also require the presence of GABA. what do they do?

they reduce instead of enhance the effectiveness of GABA

what do anesthetics do?

* strongly enhance GABA_A receptor activity
* they do it as allosteric modulators
* they differentially affect receptors with particular subunit compositions

what are neurosteroid and what do they do?

* synthesized in the brain by neurons and glia
* act as signaling molecules
* target allosteric binding sites on GABA_A receptors

What are some neurosterioids that act as GABA_A receptor positive allosteric modulators? What do they cause?

* ALLO
* THDOC
* AS
* effects
* sedation
* anxiolytic
* anticonvulsant

What are some neurosterioids that act as GABA_A receptor negative allosteric modulators? What do they cause?

* PS
* DHEAS
* effects
* opposite to the positive ones
* also + modulate NMDA receptors

what neurosterioid is involved in catamenial epilepsy (heightened seizure susceptibility during the periovulatory or perimenstrual periods) and in postpartum depression?

ALLO

What do postsynaptic GABA_B receptors do

* inhibit neuronal firing by stimulating K+ channel opening

what do presynaptc GABA_B receptors do

* can act as autoreceptors or heteroreceptors
* inhibit transmission by inhibiting Ca+2 channel opening

what does Baclofen (Lioresal) do?

* GABA_B agonist
* used as a muscle relaxant

what does Saclofen do

* antagonist at GABA_B

what doe 2-hydroxysaclofen do

* antagonist at GABA_B