Glutamate, Glycine, &

gamma-Aminobutyric Acid
(GABA)
19A
Baylon, J.L.,Caparas, E.J., Echano, J.P.,Kim, M.J., Navarro, G.J., Nioko, R.A., Palad, E.L.
● Chrmical structure 1 slide
● What are the known post synaptic receptors (incl subtypes) for the NTs
● - Are the recptors metabotropic ( g protein couples receptors) or inotropic
(ion channel receptors)? 1-2 slides
● Signaling mechanisms 1-3 slides when receptors are activated (post synaptic
or pre synaptic receptors as the case maybe) by the endogenous NTs
● Tabular summary of physiologic effects of NTs when it binds to its specific
receptors in CNS or PNS 1-3 Slides
● Drugs of abuse (when applicable) activating the NT-receptor system (1 slide)
● Include therapeutic vs potential abuse of the NT receptor system
 I. CHEMICAL STRUCTURE
GLUTAMATE

Figure 1. Chemical structure of Glutamate

 II. POST SYNAPTIC RECEPTORS
GLUTAMATE
RECEPTOR RECEPTOR SUBTYPE
Glutamate acts on both metabotropic
and ionotropic receptors IONOTROPIC
● Ionotropic receptors are named
based on their specific agonists NMDA GluNR1-NR3
● NMDA:
N-methyl-D-aspartate AMPA GluR1-R4
receptor
● AMPA: Kainate GluR5-R7,KA-1, KA-2
alpha-amino-3-hydroxy-5me
thylisoxazole-4-proprionate METABOTROPIC
● Kainate
● Metabotropic glutamate receptors Group 1 mGluR1 & R5
are G-protein coupled receptors
(GCPRs) with 8 subtypes each Group 2 mGluR2 & R3
divided into 3 groups
Group 3 mGluR4,R6, R7, & R8
 III. SIGNALING MECHANISMS
GLUTAMATE

Figure 2. Glutamate Synapse

 IV. SIGNALING MECHANISMS
GLUTAMATE

Figure 3. AMPA & Kainate receptors for Glutamate Figure 4. NMDA receptor for Glutamate
 IV. SIGNALING MECHANISMS
GLUTAMATE

Figure 5. Metabotropic Receptor for Glutamate

 IV. PHYSIOLOGIC EFFECTS
GLUTAMATE RECEPTOR PHYSIOLOGIC EFFECT

IONOTROPIC Mediate most fast EPSPs in the CNS, learning and

memory, ↑ Cation conductance ( particularly Ca2+)

NMDA

AMPA Primary depolarization, Synaptic plasticity, Excitatory

neurotransmission, Mediate most fast ESPs in the
CNS, ↑ cation conductance

Kainate Regulation of neuronal excitability

METABOTROPIC

Group I ↑IP3/DAG, ↑Ca2+

Group II ↓cAMP

Group III ↓cAMP

 IV. PHYSIOLOGIC EFFECTS
GLUTAMATE
TARGET PHYSIOLOGICAL EFFECT

CNS - Excitatory
- Serves as precursor for neuronal cells
- Main excitatory neurotransmitter of nervous system
- Learning, memory, neural communication, cognition

NON CNS - Stimulates taste (umami)

- Secretion of insulin and glucagon the pancreas
 V. DRUGS ASSOCIATED
GLUTAMATE
DRUG EFFECT DRUG EFFECT

Perampanel - Anticonvulsant drug Phencyclidine - illicit drug

- Binds to AMPA receptors
- Decrease excitatory
neurotransmission
Memantine - NMDA antagonist
- Given to Alzheimer disease patients
- Reduce glutamate induced
excitotoxicity
Ketamine - general anesthetic
- Blocks NMDA receptor
- Recreational drug
- Date-rape drug
- Binds NMDA receptors at seperate
site
- Produces dissociative and psychotic
symptoms
Riluzole - Voltage-gated channel blocker
- Antagonize NMDA receptors
- Improve life expectancy of patients
with ALS
Amantadine + - NMDA receptor antagonist
Levodopa - Improve function in patients with
Parkinson’s disease
 I. CHEMICAL STRUCTURE
GLYCINE

Figure 6. Chemical structure of Glycine

 II. POST SYNAPTIC RECEPTORS
GLYCINE

RECEPTOR RECEPTOR SUBTYPE

IONOTROPIC

Glycine Receptor (GlyR) alpha subunit: GLRA1, GLRA2,

GLRA3, GLRA4
beta subunit: GLRB

NMDA Receptor
 III. SIGNALING MECHANISMS
GLYCINE

Figure 7. Signaling Mechanism of GlyR

 III. SIGNALING MECHANISMS
GLYCINE

Figure 8.. Signaling Mechanism of NMDA

 IV. PHYSIOLOGIC EFFECTS
GLYCINE
1. Increase insulin sensitivity and regulation of blood sugar levels throughout the body
2. Increase serotonin levels and Improving sleep
- Serotonin is required to make the sleep hormone melatonin. Increasing serotonin levels can help
restore healthy sleep patterns, and encourage deeper, more restful and refreshing sleep.
- Research shows oral glycine elevates serotonin, reduces symptoms of insomnia, and improves
sleep quality.
3. Cognitive and memory enhancement
- Glycine is active in the hippocampus, an area of the brain important for memory and learning.
- Glycine appears to deliver benefits for daytime cognitive function.
4. Antioxidant
- Higher levels of glycine have been associated with a lower risk of heart attack, and there’s some
evidence that glycine may help protect against high blood pressure.
5. Regulation of the body’s immune responses
6. Glycine is one of the most important, protein-fueling amino
acids in the body.
- It supplies our muscles, bones, and connective tissues with collagen, the protein that is essential to
your strength, stability, and healthy physical function.
 V. DRUGS ASSOCIATED
GLYCINE
Strychnine
ANTAGONIST AGONIST
- Strong antagonist at ionotropic glycine
Selective - D-Alanine receptors
- Strychnine - D-Serine - Results in muscular contractions and
- Brucine - L-Alanine tetany as a result of glycinergic
- Tutin - L-Serine disinhibition and over-excitation
- Milacemide - Binding of glycine to receptors in
Non-Selective - Sarcosine postsynaptic neurons is blocked by the
- Bicucilline - Taurine poison Strychnine, thus blocking glycine’s
- Caffeine inhibitory actions
- Picrotoxin - Block of inhibition leads to hyper-excitation
- Pitrazepin and typically a patient with strychnine
- Thiocolchicoside poisoning asphyxiates due to inability to
relax the diaphragm
*Agonist stimulates the effect, being inhibitory, when glycine is bound to the
receptor.*Antagonists blocks the effect of glycine leading to excitatory.
 I. CHEMICAL STRUCTURE
GABA-AMINOBUTYRIC
ACID

Figure 9. Chemical structure of GABA

Note: GABA is known as an inhibitory

neurotransmitter for the brain.
 II. POST SYNAPTIC RECEPTORS
GAMMA-AMINOBUTYRIC ACID
RECEPTOR GABA-A GABA-B GABA-+C

LOCATION Widely distributed in Widely distributed in Retina (most)

CNS CNS

RECEPTOR TYPE Ionotropic Metabotropic Ionotropic

EFFECT Increases Cl- Increases K+ Inhibits adenyl

conductance conductance cyclase to open K+
channel &
inhibits/delays Ca2+
influx

SUBUNITS 2 α subunits GABA-B1 3 rho receptor

2 β subunits GABA-B2 subunit
1 γ subunit
*GABA-A= pentameric, GABA -B = Heterodimeric
 III. SIGNALING MECHANISMS
GAMMA-AMINOBUTYRIC ACID

Figure 10. GABA - A Receptor Mechanism

 III. SIGNALING MECHANISMS
GAMMA-AMINOBUTYRIC ACID

Figure 11. GABA - B Receptor Mechanism

 III. SIGNALING MECHANISMS
GAMMA-AMINOBUTYRIC ACID

Figure12. GABA - C Receptor Mechanism

 IV. PHYSIOLOGIC EFFECTS
GAMMA-AMINOBUTYRIC ACID
Binding of GABA to GABA-A receptor:
1. Rapid hyperpolarization due to influx of Cl-
into the cytoplasm
2. Reduces anxiety by suppressing the
circuitry in the brain that causes the
anxiety
3. Reduced dendritic excitatory
glutamatergic
4. Membrane reversal potential that is close
to, or even at a more depolarized potential
than the resting membrane potential at a
synapse also known as shunting inhibition
Binding of GABA to GABA-B receptor:
1. Gradual repolarization due to efflux of K+
from cytoplasm
2. Activation of pre-synaptic GABA-B
receptors decreases neurotransmitter
release by inhibiting voltage-activated
Ca2+ channels
3. Stimulates the modulated production of
cAMP
- leads to a wide range of actions on ion
channels as well as other proteins that are
targets of PKA cAMP modulation by
GABA-B receptors effects modulation of
both neuronal and synaptic functions
 V. DRUGS ASSOCIATED
GAMMA-AMINOBUTYRIC ACID

Agonists Antagonists

Alcohol Beta lactam Antibiotics

Barbiturates Flumazenil

Benzodiazepines Gabazine

Etomidate Saclofen

Propofol