Glycine receptor

thumb|class=skin-invert-image|[[Glycine]]

The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride currents. It is one of the most widely distributed inhibitory receptors in the central nervous system and has important roles in a variety of physiological processes, especially in mediating inhibitory neurotransmission in the spinal cord and brainstem.

The receptor can be activated by a range of simple amino acids including glycine, β-alanine and taurine, and can be selectively blocked by the high-affinity competitive antagonist strychnine. Caffeine is a competitive antagonist of GlyR. Cannabinoids enhance the function.

The protein Gephyrin has been shown to be necessary for GlyR clustering at inhibitory synapses. GlyR is known to colocalize with the GABAA receptor on some hippocampal neurons. Nevertheless, some exceptions can occur in the central nervous system where the GlyR α1 subunit and gephyrin, its anchoring protein, are not found in dorsal root ganglion neurons despite the presence of GABAA receptors.

History

Glycine and its receptor were first suggested to play a role in inhibition of cells in 1965. Two years later, experiments showed that glycine had a hyperpolarizing effect on spinal motor neurons due to increased chloride conductance through the receptor. Then, in 1971, glycine was found to be localized in the spinal cord using autoradiography. All of these discoveries resulted in the conclusion that glycine is a primary inhibitory neurotransmitter of the spinal cord that works via its receptor.

Arrangement of subunits

thumb|class=skin-invert-image|(a): shows three agonists and one antagonist of the glycine receptor. (b): the fetal form of the receptor is made up of five α2 subunits, while the adult form is made up of both α1 and β subunits.

Strychnine-sensitive GlyRs are members of a family of ligand-gated ion channels. Receptors of this family are arranged as five subunits surrounding a central pore, with each subunit composed of four α helical transmembrane segments. There are presently four known isoforms of the ligand-binding α-subunit (α1-4) of GlyR (GLRA1, GLRA2, GLRA3, GLRA4) and a single β-subunit (GLRB). The adult form of the GlyR is the heteromeric α1β receptor, which is believed to have a stoichiometry (proportion) of three α1 subunits and two β subunits or four α1 subunits and one β subunit. The embryo form on the other hand, is made up of five α2 subunits. The α-subunits are also able to form functional homopentamers in heterologous expression systems in African clawed frog oocytes or mammalian cell lines, which are useful for studies of channel pharmacokinetics and pharmacodynamics.

Function

Adults

In mature adults, glycine is an inhibitory neurotransmitter found in the spinal cord and regions of the brain. As the channel opens, chloride ions are able to flow into the cell which results in hyperpolarization. In addition to this hyperpolarization, which decreases the likelihood of action potential propagation, glycine is also responsible for decreasing the release of both inhibitory and excitatory neurotransmitters as it binds to its receptor. This is called the "shunting" effect and can be explained by Ohm's law. As the receptor is activated, the membrane conductance is increased and the membrane resistance is decreased. According to Ohm's law, as resistance decreases, so does voltage. A decreased postsynaptic voltage results in a decreased release of neurotransmitters.

Ligands

Agonists

β-Alanine
D-Alanine
Gelsemine
Glycine
Hypotaurine
Ivermectin
L-Alanine
L-Proline
L-Serine
Milacemide
Quisqualamine
Sarcosine
Taurine
THC
L-Theanine

Positive Allosteric Modulators

Ethanol
Toluene
Zonisamide

Antagonists

Bicuculline
Brucine
Caffeine
Levorphanol
Picrotoxin
Strychnine
Tutin
Quercetin
Tranexamic acid