Neurotransmitters Systems II: GABA & Glycine (Physiology 2)

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS.

Its primary role is to prevent excessive neuronal activity and maintain balance in the nervous system.

GABA was first identified in the mammalian nervous system by Eugene Roberts in 1950.

In 1957, GABA was shown to inhibit action potential firing in crayfish neurons.

GABA is recognized as the major inhibitory neurotransmitter in the human brain.

Approximately one-third of synapses in the brain utilize GABA as their neurotransmitter.

GABA is most commonly found in local circuit interneurons as an inhibitory neurotransmitter.

Glutamate is the precursor molecule for GABA synthesis.

The enzyme responsible for synthesizing GABA from glutamate is Glutamate Decarboxylase (GAD).

Pyridoxal phosphate, derived from vitamin B6, is required as a co-factor for GABA synthesis.

GABA is synthesized in the nerve terminals of neurons.

GABA is transported into vesicles by Vesicular Inhibitory Amino Acid Transporters (VIAAT) and stored in round and oval-shaped vesicles.

The first step in GABA degradation is the conversion of GABA into Succinic semialdehyde by the enzyme GABA transaminase (GABA-T).

Succinic semialdehyde dehydrogenase (SSADH) is responsible for converting Succinic semialdehyde into Succinic acid.

High-affinity Na+ dependent GABA re-uptake transporters (GATs) are involved in the re-uptake of GABA.

GAT-1 is found in neurons.

GAT-3 is found in glial cells.

Ligand-gated ion channels (ionotropic)

G-protein coupled receptors (metabotropic)

GABA binds at both ionotropic and metabotropic GABA receptors.

Ligand-gated Cl⁻ channel

Pentameric structure, commonly composed of 2α, 2β, and γ subunits, with other possible subunits (δ, ε, π, θ)

Opens to allow Cl⁻ ions to flow, causing inhibitory postsynaptic potentials (IPSPs) and hyperpolarization of the postsynaptic neuron.

Agonist/antagonist binding site (e.g., GABA)

Additional binding sites for benzodiazepines, channel blockers (e.g., picrotoxin), channel modulators (e.g., GA), and allosteric modulators (e.g., barbiturates)

GABA₋B is a G-protein coupled receptor (GPCR) with a 7-transmembrane domain

It functions as a dimer, composed of GABAB1 and GABAB2 subunits

It primarily signals via Gi/o proteins to modulate K⁺ and Ca²⁺ ion channels

Inhibitory neurotransmitters, such as GABA, bind to receptors and cause the opening of ion channels.

This leads to an influx of Cl⁻ ions or efflux of K⁺ ions, which makes the membrane potential more negative, resulting in hyperpolarization.

The cerebellum detects differences between the intended movement and the actual movement, helping to correct motor errors.

The cerebellum works with the motor cortex to produce precise and coordinated movements.

The cerebellum is involved in the synchronization of movement with musical rhythm.

Yes, the function of the cerebellum is conserved across the animal kingdom.

The cerebellum accounts for approximately 10% of the human brain's volume.

Purkinje cells are GABAergic neurons and the principal projection neurons of the cerebellar cortex.

Purkinje cells have elaborate dendritic trees that receive convergent input from cells in the molecular layer.

Purkinje cells send GABAergic projections to deep cerebellar neurons.

The output of Purkinje cells to deep cerebellar neurons generates an error connection signal that can modify movements.

Purkinje cell output provides the basis for the real-time control of precise and synchronous movement.

Glutamate and GABA are the major neurotransmitters controlling the brain's overall level of excitation.

Disruption in the balance of GABA and glutamate can lead to neurological or psychiatric disorders due to altered excitation and inhibition in the brain.

Glutamate is converted into GABA by the enzyme glutamate decarboxylase (GAD), with pyridoxal phosphate (derived from vitamin B6) as a co-factor.

Epilepsy is a brain disorder characterized by periodic and unpredictable seizures caused by the rhythmic firing of large groups of neurons.

In epilepsy treatment, enhancing GABAergic neurotransmission can help increase inhibition to counteract excessive neuronal excitation.

GABAₐ receptor enhancers (e.g., Barbiturates, Benzodiazepines)

GAT blockers (e.g., Tiagabine)

GABA-transaminase inhibitors (e.g., Vigabatrin)

GAD modulators (e.g., Gabapentin, Valproate, Progabide)

In epilepsy treatment, the general approach is to increase inhibition (through GABAergic agents) to counteract excessive excitation in the brain.

Anxiety is a feeling of unease, such as worry or fear, which can range from mild to severe.

Generalized anxiety disorder and panic disorder are examples of anxiety disorders.

Anxiolytics are medications used to reduce anxiety.

An example of an anxiolytic is benzodiazepines, which target the GABAₐ receptor.

Glycine is the second major inhibitory neurotransmitter in the CNS.

Glycine was first identified in the spinal cord and brainstem in 1965.

In 1967, glycine was shown to inhibit action potential firing in spinal neurons.

Glycine is most commonly found as an inhibitory neurotransmitter in the ventral horn, where spinal interneuron terminals are located.

Our understanding of the glycine receptor is behind that of the GABA receptor because there are fewer substances that can modify its function in different ways (known as allosteric modulators).

Glycine is synthesized from 3-phosphoglycerate, which is a product of glycolysis.

The enzyme serine hydroxymethyl-transferase is responsible for converting serine to glycine.

Glycine is synthesized in the nerve terminals.

It is transported into vesicles by vesicular inhibitory amino acid transporters (VIAAT) and stored in oval vesicles.

GlyT-1 is found in glial cells.

GlyT-2 is found in neurons.

Both are high-affinity, Na+ dependent transporters responsible for glycine re-uptake.

Glycine degradation is carried out by various enzymes.

One key enzyme involved is serine hydroxymethyl-transferase, which is also involved in the reversal of glycine biosynthesis.

The glycine receptor is a ligand-gated Cl⁻ channel with a pentameric structure.

It consists of four α subtypes (α1–α4) and one β subtype.

The most common configurations are 3α1β or 4α1β.

The agonist/antagonist binding sites on the glycine receptor are not fully understood.

Strychnine, a plant alkaloid, potently blocks glycine receptors.

Glycine activity is terminated through reuptake by the glycine reuptake transporter (GlyT).

Hyperekplexia is a rare disorder characterized by hypertonia (increased muscle tone) and an exaggerated startle response.

Symptoms can be triggered by unexpected stimuli, such as loud noises.

Gene mutations in glycine receptors or glycine transporters can disrupt normal glycinergic neurotransmission.

This disruption can lead to neuronal hyperexcitability by impairing glycinergic inhibition, contributing to the symptoms of hyperekplexia.

Decreased muscle chloride conductance is the primary cause of the startle response in myotonic goats.

This decreased conductance can be caused by glycine receptor mutations.

As the goats mature, GABA receptors are upregulated to compensate for the disrupted glycine receptor function.

Hyperpolarisation is a change in a cell's membrane potential that takes it further away from 0mV.

Glutamate decarboxylase (GAD) is the enzyme that mediates the conversion of glutamate to GABA.

GABA is a major inhibitory neurotransmitter in the central nervous system (CNS).

Glycine is another major inhibitory neurotransmitter in the central nervous system (CNS).

The VIAAT is responsible for sequestering (isolating and storing) GABA and glycine into vesicles from the cytosol in the presynaptic bouton.

The GABA reuptake transporter (GAT) is responsible for sequestering (isolating and storing) GABA into the presynaptic bouton from the cytosol.

GABA transaminase is the enzyme that breaks down GABA in the synaptic cleft.

Panspermia is the theory that the universe contains the materials for the ‘building blocks’ of life.

Glycine decarboxylase is the enzyme that breaks down glycine in the synaptic cleft.

The Glycine reuptake transporter (GlyT) is responsible for sequestering glycine into the presynaptic bouton from the cytosol.