GABA and Glycine

GABA

- major inhibitory aa NT in mature CNS

- locations = brain and spinal cord (major), peripheral tissues (lungs, intestines, etc.)

GABA synthesis

derived by decarboxylation of Glu by glutamic acid decarboxylase (GAD)

glutamic acid decarboxylase (GAD)

key enzyme and rate limiting step

Glycine

- smallest aa and achiral

- precursor and building block for proteins (i.e. collagen)

- forms key step in biosynthesis of porphyrins (heme) and purines

Glycine synthesis

biosynthesized from serine via hydroxy methyltransferase

GABA transporters

- sodium- and chloride-dependent reuptake transporters found in neurons and glia

- Terminates GABA signaling by co-transporting GABA with Na⁺ and Cl⁻ into the cell.

- Utilizes the movement of Na⁺ and Cl⁻ down their electrochemical gradients for transport

- hydrophobic, 12 transmembrane proteins w/ high sequence homology

Type 1 (GAT1)

- found in brain cell membranes

- high affinity for GABA

Type 2 (GAT2)

- mostly in liver, kidneys

- low concentration in meninges

Type 3 (GAT3)

- found in glial cells

- terminates GABA signaling in neighboring synapse by uptake

Betaine transporter (BGT1)

- ancient protein found in bacteria, similar to GAT2

- low affinity for GABA

- primarily transports betaine class chemicals (ex: glycine betaine)

Glycine transporters (GlyT1 and GlyT2)

- Plasma membrane proteins in neurons that terminate glycine signaling through electrogenic ion co-transport.

- Require three Na⁺ and one Cl⁻ to move one glycine molecule into the presynaptic neuron for repackaging.

vesicular GABA transporter (VGAT)

- similar structure to VGKUT, but highest affinity for GABA and Gly

- creates pH gradient → 2H+ for 1 GABA/Gly

- works fast

Gly fate

repackaged or degraded (via Gly cleavage enzyme)

GABA fate

- presynaptic = recycled into vesicle or metabolized

- glial = metabolized via transamination of alpha-ketoglutarate (catalyzed by GABA transaminase)

GABA-A receptor

- pentameric ion channel

- fast inhibition (↑ Cl- conductance influx = inhibitory)

- allosteric modulation: benzodiazepines, barbiturates, ethanol, steroids

- muscimol

GABA-B receptor

heterodimer metabotropic receptor that’s inhibitory (ex: Balcofen = agonist)

GABA-C receptor

- narrow distribution; all p-subunits

- inhibitory ion channel, insensitive to allosteric modulation

Glycine receptors

- composed of subunits (4alpha, Beta) = pentameric channel

- fast inhibitory (↑ Cl- conductance influx)

- ethanol = + allosteric modulator and strychnine antagonist

hyperekplexia

- caused by mutation of alpha 1 subunit in Gly receptor

- rare genetic condition defect that results in exaggerated startle reflex + ↑ rigidity at birth

major effects of Gly

analgesia, motor coordination, schizophrenia, sleep

analgesia

GlyR activation in substantia gelatinosa of spinal cord inhibits nociceptive input in lamina 1 and 2

motor coordination (ref. GlyR)

GlyR activation in brainstem and spinal cord smooths locomotor output

Schizophrenia (ref. GlyR)

↑ NMDA, GlyT1 inhibitors in clinical trials for negative symptoms

sleep (ref. GlyR)

Glycine (3g nightly) found to improve sleep quality

GABAergic pathways

- striatum → substantia nigra (inhibits dopamine signaling, ↓ locomotion, reward)

- substantia nigra → colliculus (prevents locomotor activity)

GABA effects

- analgesia → inhibit nociception in brain

- inhibits descending pathway in midbrain PAG which regulates nociceptive relay neurons

- opioids → ↑ descending control + analgesia

GABA interneurons

control neuronal excitability:

- Postsynaptic inhibition = ↑ Cl- hyperpolarizes neuron, ↓ EPSP

- presynaptic inhibition = GABA-A ↑ Ca2+, causing ↓ NT release

GABA agonists

produce sedation

GABA antagonists

produce convulsions → induce seizures and feelings of anxiety/dread

epilepsy (ref. GABA)

- increase in GABAergic signaling inhibits neuronal activity correlated w/ seizures 

- GABA agonists, PAM (BDZ) = antiepileptic + anticonvulsants 

anxiety (ref. GABA)

- GABA + allosteric modulation (benzodiazepines, barbiturates, ethanol) are all anxiolytics 

- ↑ GABA activity = ↓ locus ceruleus output and inhibition of amygdala/hippocampus

Sedation (ref. GABA)

- PAM or GABA agonists suppress neuronal firing → calming w/o sleep (hypnotic effects = produced drowsiness, promote sleep)

Motor function (ref. GABA)

- inhibit locomotor activity, especially at substantia nigra (ex: Huntington’s disease)

- cerebellum = highly organized brain structure, works to coordinate and refine locomotor output (5/6 are GABAnergic)

Muscimol

GABA-A agonist, sedative found in mushrooms