Lectures 7 & 8 - Intro to brain - glutamate & GABA

What is glutamate

Main excitatory transmitter in CNS

synthesised from glutamine 

activate large family of ionotropic and metabotropic receptor 

what is GABA

Main inhibitory transmitter

synthesized from glutamate

glycine (amino acid transmitter)

activates a large family of inotropic and metabotropic receptors

Glutamate

amino acid aspartate

GABA

Amino acid glycine 

Where is glutamate found

Pyramidal neurones

neurones shaped like a pyramid

Where is GABA found

interneurons (shorter local)

projection neurones

Where is glutamate synthesised from

glucose in krebs cycle

or

glutamine in gilal cells

How is glutamate converted

contains GAD which converts glutamate to GABA

•Glutamate can be converted to GABA by the enzyme glutamic acid decarboxylase – GAD

How is glutamate metabolisd

• stored in synaptic vesicles inside neurons, and released into the synapse when calcium signals trigger exocytosis.

• Once released, excess Glu is quickly cleared by EAAT transporters, which move it into neurons and astrocytes (supporting glial cells).

• In astrocytes, Glu is converted into glutamine (Gln) by the enzyme glutamine synthase.

• Glutamine (Gln) is transported back into neurons by GlnT transporters.

• In the neuron, glutaminase converts glutamine back into glutamate, ready to be used again.

• Before release, glutamate is packaged into vesicles by Vesicular Glutamate Transporters (VGlutT).

How is GABA metabolised

• Start with glucose (energy source):

  • Glucose enters the TCA cycle (Krebs cycle).

  • Through glycolysis and acetyl-CoA, it produces α-ketoglutarate, a key intermediate.

• Formation of Glutamate:

  • α-ketoglutarate is converted into glutamate (an excitatory neurotransmitter).

• Synthesis of GABA (inhibitory neurotransmitter):

  • Glutamic acid decarboxylase (GAD) converts glutamate → GABA.

  • This is the main pathway of GABA production.

• Breakdown of GABA:

  • GABA is broken down by the enzyme GABA transaminase into succinic semialdehyde.

  • (💡 Drugs that inhibit GABA transaminase, like vigabatrin, increase GABA levels and are used in epilepsy treatment.)

• Entry back into TCA cycle:

  • Succinic semialdehyde is converted into succinate by succinic dehydrogenase.

  • Succinate re-enters the TCA cycle, closing the loop.

Describe the function and structure of ionotropic receptors

•Multisubunit receptors

•Heterogeneous receptors (not same subunit)

•Affects physiological function and pharmacology

•Rapid cellular effects

aka LIGAND GATED ION CHANNELS

Describe the function and structure of metabotropic receptors

•Hetero- and homodimers

•Activate second messenger systems

• effects on synaptic transmission

•May be “autoreceptors” located presynaptically on nerve terminals

aka g-protein coupled

Describe GABA A

Chloride ion channel

inhibitory

Gaba B

7 transmembrane protein coupled to trimeric g alpha, g beta and g gama protein

inhibitory

Gaba C

chloride ion channel

inhibitory

Describe the structure of ionotropic GABA receptors

pentameric 

6 different alpha

3 beta

3 gamma

1 gamma

1 e

3 P

ligang gated

fast hyperpolarisation→ inhibition

Where are the main sits of drug action on GABA a receptors

Orthosteric : receptor site e.g. gaba agonists, channel blocking drugs

Allosteric site: modulatory site: benzodiazipine agonists, antagonists, benzodiazepine inverse agonists, channel modulators

how do gaba receptors induce an inhbitory effects

chloride ions enter the channel 

create more negative 

moves action potential away from threshold 

What anesthetics are GABA

  e.g. etomidate & propofol are volatile anaesthetics that act at GABA_ARswhat

are barbituates

  e.g. pentobarbital has sedative/anticonvulsant effectswh

what are benzodiazpine

  Multiple actions e.g. anxiety relieving, anticonvulsant, hypnotic

what are neurosteroids

•Neurosteroids -Metabolites of progesterone & deoxycorticosterone

Describe how is gaba heterodimer

contains R1 and R2

closes ca2+ channels presynaptically to reduce transmitter release

autoreceptor

Open potassium channels postsynaptically eliciting a slow hyperpolarization

spacisity

rigidity in muscles and limbs

Iono glutamate receptors

tetrameric

NMDA: 7 subunits

AMPA:

KAINATE:

How do glutamate receptors induce excitatory response

Sodium enters channel pore

creates more positivity

drives action potential closer to threshold

excitatory postsynaptic potential

fast excitatory neurotransmission

how do NMDA receptors work

cell depolarised

Mg2+ block is removed 

activation requires glycine and glutamate 

examples: ketamine, memantine 

metabotropic glutamate receptors

8 different G-protein coupled receptors

group 1, group 11, group 111

slow neuromodulatory role

no drugs on the market

glutamate presynaptically

increases glutamate release through NMDAr

Presynaptic mGluR decreases glutamate release by decreasing ca2+

how does glutamate bind to so many receptors

its not a rigid molecle rotates about aB and By bonds

has different conformations 

nine rotamers