Inhibitory neurotransmitters

GABAergic neurons

GABA release and its subsequent actions play a crucial role in regulating the balance between excitation and inhibition in the nervous system, influencing the overall activity of neural circuits. GABAergic neurons are nerve cells that release GABA as their primary neurotransmitter. The majority of local circuit neurons in the central nervous system (CNS) are GABAergic interneurons but many projection neurons are GABAergic as well. Typical examples of these neurons are cortical interneurons, neurons of the reticular nucleus of the thalamus, medium sized spiny neurons of the striatum, neurons of the globus pallidus and substantia nigra pars reticulata, and Purkinje cells of the cerebellum.

GABA synthesis and release

GABA predominates as the principal inhibitory neurotransmitter within the CNS and is synthesized in the cytoplasm of the GABAergic neurons, typically from the decarboxylation of its precursor neurotransmitter glutamate by the enzyme glutamate decarboxylase (GAD). There are two isoforms of GAD, GAD65 and GAD67, each named after their respective molecular weights.

Once synthesized, GABA is stored in vesicles, small membrane-bound sacs within the axon terminals. When an action potential reaches the terminal, it triggers the release of GABA into the synapse. This is achieved through a process called exocytosis, where the vesicle membrane fuses with the cell membrane, releasing the neurotransmitter into the synapse. After GABA is released, it binds to GABA receptors on the postsynaptic membrane.

Neurotransmitters are an important part of the nervous system. Learn more about the anatomy of the nervous system with our beginner-friendly quizzes and labeled digrams.

GABA receptors

There are two main types of GABA receptors:

• GABA-A receptors. GABA-A receptors are ligand-gated ion channels. They open in response to the binding of GABA, allowing chloride ions to flow into the neuron. This influx of chloride ions hyperpolarizes the neuronal membrane, making it less likely to depolarize and reducing the overall excitability of the neuron.
• GABA-B receptors. GABA-B receptors are metabotropic receptors and exert their effects through G-proteins. When GABA binds to GABA-B receptors, it activates a signaling pathway that involves the inhibition of adenylyl cyclase and the opening of potassium channels. Potassium ions flow out of the neuron, driven by their electrochemical gradient and hyperpolarize the cell membrane, inhibiting the postsynaptic neuron. GABA-B receptors can be also found in the axon terminals on the presynaptic membrane, playing a role in presynaptic inhibition, modulating the release of neurotransmitters such as glutamate and GABA itself.

GABA reuptake

Every time GABA is released in the synaptic cleft of a synapse, its effects terminate by reuptake or enzymatic degradation. Reuptake is the reabsorption of neurotransmitters by the presynaptic neuron. GABA can be taken back up into the axonal terminal or into the processes of nearby glial cells by specialized proteins called GABA transporters that actively pump GABA molecules from the synaptic cleft. Alternatively, GABA can be broken down by enzymes in the synaptic cleft, like GABA transaminase.
The reuptake of GABA serves several important functions:

• Termination of signal: Reuptake helps terminating the GABAergic signal by removing GABA from the synaptic cleft. This is crucial for preventing continuous inhibition of the postsynaptic neuron.
• Preservation of GABA: Reuptake allows the presynaptic neuron to recycle GABA for future use. This is an energy-efficient way to maintain a pool of neurotransmitters for ongoing neurotransmission.
• Prevention of spillover: Reuptake helps prevent the spillover of GABA to neighboring synapses, ensuring that the neurotransmitter is specifically acting on the intended postsynaptic receptors.

There are different subtypes of GABA transporters responsible for GABA reuptake, and they play a role in regulating the concentration of GABA in the synaptic cleft. Drugs that affect GABA reuptake could potentially influence GABAergic neurotransmission and are areas of interest in research for conditions where GABAergic signaling is disrupted.

It's important to note that the process of reuptake is very specific for every neurotransmitter. So, GABA transporters are distinct from the transporters for other neurotransmitters like serotonin, dopamine, and norepinephrine, and involve different mechanisms.

GABA agonists

GABA agonists are substances that bind and activate GABA receptors in the CNS. GABA agonists are used in clinical practice as medications that can have various effects on the nervous system, including calming or sedative effects. Benzodiazepines are a class of medications that enhance the inhibitory effects of GABA-A receptors. Examples include diazepam, lorazepam, and alprazolam. Barbiturates are another class of drugs that act as GABA agonists. Ethanol, the active ingredient in alcoholic beverages, has complex effects on the GABAergic system. It enhances the inhibitory effects of GABA-A receptors, contributing to its sedative and anxiolytic properties. Some muscle relaxant medications, such as baclofen, act as GABA-B receptor agonists. Baclofen is used to treat muscle spasms and spasticity.

Glycine structure

Glycine is the simplest amino acid both structurally and chemically. It can be synthesized from the amino acid serine by the serine hydroxymethyltransferase or or produced by the glycine synthase. Glycine has a nonpolar side chain with a hydrogen atom and its chemical formula is H₂N-CH₂-COOH.

Glycine mechanism of action

In the CNS, glycine serves as an inhibitory neurotransmitter, found particularly in the spinal cord and brainstem. Its action is mediated by glycine receptors (GlyRs), which are ionotropic chloride receptors. The binding of glycine to the receptor causes the opening of the channel, resulting in an influx of chloride ions. This leads to the hyperpolarization of the postsynaptic membrane, which makes it more difficult for the neuron to generate an action potential, thus contributing to inhibitory neurotransmission.

GlyRs consist of five subunits that form pentamers with a central ion-conducting pore. Two main types of GlyR subunits have been described. Subunit α determines the receptor's pharmacological and physiological properties, with four different isoforms. Subunit β is important for receptor assembly and functional expression. Glycinergic neurotransmission also depends on the reuptake of glycine from the synaptic cleft by the presynaptic membrane through glycine transporters (GlyTs)