Photo: AI-generated image created by Prof. Blundell

Throughout the timeline of mammalian evolution, higher brain function can be considered as the attribution to some mammalian species' advancement within the hierarchies of various ecosystems. An integral part of such high neurocognition is attributed to the effectiveness of intercellular communication within the brain and the nervous system, which is facilitated by receptors, such as glycine receptors.

What is the function of the glycine receptor?

The glycine receptor functions as a pathway through which chloride ions are allowed to permeate, thus allowing inhibitory neurotransmission to occur at a fast pace. With these types of receptors being a key factor in the glycinergic system, glycine receptors are able to control certain crucial physiological functions namely, pain signalling, motor coordination and even respiration rhythm regulation. An additional function of a glycine receptor is its contribution to the central nervous system's embryological development in terms of morphology development, neuron migration and cell cycle control.

Where are the glycine receptors found?

Glycine receptors are found within the peripheral and central nervous systems, with the latter comprising of the spinal cord as well as the brainstem. Furthermore, there has been evidence of such receptors to co-exist with gamma-aminobutyric acid (GABA) receptors within certain mammalian species' retinas. The co-existence of glycine and GABA receptors, also known as a mixed synapse, within amacrine cells in the retina of mice, was found to have a dual-presynaptic co-release sites for glycine and GABA neurotransmitters, respectively. With regards to the distribution of the glycine receptors, the function of glycine receptors found within the spinal cord is affected by the receptors' embryonic origin. Glycine receptors were also found to contribute to blood flow regulation due to their distribution within the renal cortex and medulla and furthermore, the hypothalamus, amygdala, striatal regions and the cortex were found to have the highest expression of a subtype of glycine receptor called alpha-3 glycine receptors.

Glycine as a neurotransmitter

Fast inhibitory neurotransmission is brought about in a glycine receptor by its full agonist; glycine. Termed as the simplest amino acid, glycine causes hyperpolarisation within the glycine receptor. When the receptor is hyperpolarised, the ion channel would open and allow chloride ions to pass through which in turn causes the neurotransmission to continue its course through neurons. Glycine is synthesised endogenously in both the liver and kidney of the body and this neurotransmitter acts as a positive modulator of the glycine receptor which leads to neuron excitation and causes plasticity in synapses that are glutaminergic. There are several other roles that glycine has within the body. Such roles include the production of

purine and collagen, anti-inflammation, pain transmission, restoration of tissue as well as muscle tone improvement, among many others. There are two transporters that keep glycine in homeostasis in the body and these are glycine transporter 1 and glycine transporter 2.

Glycine Receptor Structure

The structure of a glycine receptor comprises of a chloride channel that is ligand gated.

There are 5 subunits that make up the receptor, 4 alpha (α) subunits and one beta (β) subunit, hence this receptor is described as a pentameric receptor. The receptor is also composed of transmembrane domains 1- 4, a large extracellular domain and short extra-cellular C-terminus. This receptor is classified as part of the Cys-loop superfamily. There are two subtypes of glycine receptors and these are either heteromeric where the receptor is made up of both alpha and beta subunits or homomeric, where the receptor is only comprised of alpha subunits. Heterometric receptors that are found in postsynaptic neurons present with a stoichiometry of four alpha subunits to one beta subunit. Homomeric receptors are found mainly in presynaptic neurons. The different subunits aid in promoting various functions. The alpha subunit α3 is crucial for breathing control and hearing and found abundantly in the spinal dorsal horn for nociceptive system processing. The α2 subunit crucial for cortical migration, neurogenesis and memory recognition while α1 subunit is crucial for essential physiological functions and it is mainly found in spinal cord and brainstem. The beta subunit is important in aiding heteromeric glycine receptors to cluster together whilst also facilitating synapse stabilisation through the interaction with a scaffold protein called gephyrin.

The receptor's synaptic mechanism occurs when glycine initiates hyperpolarisation through an influx of chloride ions by having this neurotransmitter bind to the receptor. When hyperpolarised, the glycine receptor can transition between three states with the aid of antagonists, agonists and kinetics. The three states are open, desensitised and closed, and the receptor can shift from one stage to another.

Factors affecting glycine receptor

There are many factors affecting the activity of the glycine receptor. The scaffold protein gephyrin which is associated with the beta subunit, can influence both receptor clustering and stabilisation. Whilst glycine acts as an agonist to the glycine receptor, strychnine acts as the antagonist hence lower the receptor activity. Picrotoxin acts as channel blocker to the receptor hence does not allow chloride ions to pass through and ivermectin on the other hand, potentiates the receptor and enhance glycine sensitivity.

There are also many chemicals that can be used as endogenous modulators of glycine receptors. There are partial agonists such as GABA, taurine and β-alanine which produce an effect on the receptor that is less than maximal as opposed to the full agonist for this receptor which is glycine. Zinc is a special allosteric modulator, with a unique affect on neurotransmission of the central nervous system, as it acts as a bidirectional modulator where it can both inhibit and potentiate glycine receptor activity, depending on the concentration of zinc available. Ethanol is potentiator of glycine receptor however it is known to have different allosteric modulation on the glycine receptor homomers and heteromers.

There are also certain endogenous modulators of the glycine receptor that are used as pharmaceuticals. Zonisamide, an antiepileptic drug used for temporal lobe epilepsy treatment is a non-selective positive allosteric modulator of glycine receptor while tropeines, which are antagonists of the receptor are used as antiemetics. Endocannabinoids are used pharmacologically for their anti-nociceptive, anti- convulsant, anti-psychotic, anti-emetic and antioxidant effects whilst also providing an inhibitory, inactivation and potentiation of glycine receptor. THC and CBD have also shown to restore function of glycine receptor in cocaine-induced seizures. Sulfonamide which is a positive allosteric modulator and a potentiator of the receptor is used in the pharmaceutical industry for its antibiotic properties.

Clinical applications

Glycine receptors are considered as clinically relevant as there is a connection between such receptor types and a variety of neurological disorders. In order to treat such disorders, there is currently a lot of research done that is focused on developing therapies that specifically target the different subunits and subtypes of glycine receptors. There is growing interest in the relationship between alpha 1 and alpha 2 glycine receptors and chronic pain and nociception because mutations in such alpha subunits have been found to influence pain threshold. When glycine receptor function is disrupted, it can result in startle disorders such as hyperekplexia and when there are mutations in alpha 2 subunit that code for loss of function in the receptor, it has been reported that such loss of function is associated with autism spectrum disorder. Whilst zonisamide, a non-selective positive allosteric modulator of glycine receptor, is used pharmaceutically as an antiepileptic drug, the link found between  temporal lobe epilepsy and glycine receptor autoantibodies needs to further studied. There have also been studies that suggest that glycine receptor plays a role in certain autoimmune diseases such the high anxiety associated with Alzheimer's disease and stiff person syndrome.

In conclusion, glycine receptors are being studied more for their clinical relevance in relation to neurological disorders. However, further studies need be carried out to better understand the relationship between glycine receptors and neurological disorders, so that more efficient and novel therapeutic management techniques are developed, ones that target these crucial receptors.

Renald Blundell is a biochemist and biotechnologist with a special interest in Natural and Alternative Medicine. He is a professor at the Faculty of Medicine and Surgery, University of Malta.

Nicole Mizzi graduated with a BSc. (Hons) in Biology and is currently a medical student at the University of Malta.