Gephyrin

Gephyrin is a is_associated_with::protein that in humans is encoded by the GPHN is_associated_with::gene.

This gene encodes a neuronal assembly is_associated_with::protein that anchors inhibitory is_associated_with::neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and is_associated_with::tubulin dimers. In nonneuronal tissues, the encoded protein is also required for is_associated_with::molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition is_associated_with::hyperekplexia and also lead to is_associated_with::molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known.

Function
Gephyrin is a 93kDa multi-functional is_associated_with::protein that is a component of the postsynaptic protein network of is_associated_with::inhibitory synapses. It consists of 3 domains: N terminal G domain, C terminal E domain, and a large unstructured linker domain which connects the two. Although there are structures available for trimeric G and dimeric E domains, there is no structure available for the full length protein, which may be due to the large unstructured region which makes the protein hard to crystallize. But a recent study of the full length gephyrin by is_associated_with::small-angle X-ray scattering shows that it predominantly forms trimers, and that because of its long linker region, it can exist in either a compact state or either of two extended states.

Positive antibody staining for gephyrin at a synapse is most of the time consistent with the presence of is_associated_with::glycine and/or GABAA receptors. Nevertheless, some exceptions can occur like in is_associated_with::neurons of Dorsal Root Ganglions where gephyrin is absent despite the presence of GABAA receptors. Gephyrin is considered a major scaffolding protein at inhibitory synapses, analogous in its function to that of is_associated_with::PSD-95 at glutamatergic synapses. Gephyrin was identified by its interaction with the is_associated_with::glycine receptor, the main receptor protein of inhibitory synapses in the spinal cord and brainstem. In addition to its interaction with the glycine receptor, recent publications have shown that gephyrin also interacts with the intracellular loop between the transmembrane helices TM3 and TM4 of alpha and beta subunits of the GABAA receptor.

Gephyrin displaces GABA receptors from the is_associated_with::GABARAP/P130 complex, then brings the receptors to the synapse. Once at the synapse, the protein binds to is_associated_with::collybistin and neuroligin 2. In cells, gephyrin appears to form is_associated_with::oligomers of at least three subunits. Several is_associated_with::splice variants have been described that prevent this oligomerization without influencing the affinity for receptors. They nevertheless affect the composition of inhibitory synapses and can even play a role in diseases like epilepsy.

The gephyrin protein is also required during is_associated_with::molybdenum cofactor assembly for insertion of is_associated_with::molybdenum.

Clinical significance
Humans with is_associated_with::temporal lobe epilepsy have been found to have abnormally low levels of gephyrin in their temporal lobes. In animal models, a total lack of gephyrin results in stiff muscles and death immediately after birth. Stiff muscles are also a symptom of startle disease, that can be caused by a mutation in the gephyrin gene. And if a person produces auto-antibodies against gephyrin, this can even result in is_associated_with::stiff person syndrome.

Interactions
GPHN has been shown to interact with is_associated_with::Mammalian target of rapamycin and is_associated_with::ARHGEF9.