GPHN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1JLJ
Identifiers
Aliases	GPHN, GEPH, GPH, GPHRYN, HKPX1, MOCODC, gephyrin
External IDs	OMIM: 603930 MGI: 109602 HomoloGene: 10820 GeneCards: GPHN
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q23.3-q24.1 Start 66,507,407 bp[1] End 67,181,803 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12|12 C3 Start 78,273,153 bp[2] End 78,731,546 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cerebellar cortex cerebellar hemisphere right lobe of liver prefrontal cortex caudate nucleus nucleus accumbens dorsolateral prefrontal cortex Brodmann area 9 putamen amygdala Top expressed in spermatid extensor digitorum longus muscle saccule mammillary body plantaris muscle cerebellar vermis triceps brachii muscle otic placode sternocleidomastoid muscle olfactory tubercle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding molybdopterin molybdotransferase activity metal ion binding protein binding catalytic activity molybdopterin adenylyltransferase activity ATP binding nitrate reductase activity molybdopterin cofactor binding Cellular component cytoplasm postsynaptic membrane membrane plasma membrane synapse cell junction cytoskeleton cell projection dendrite postsynaptic density cytosol postsynaptic specialization postsynaptic specialization membrane Biological process gamma-aminobutyric acid receptor clustering glycine receptor clustering Mo-molybdopterin cofactor biosynthetic process molybdenum incorporation into molybdenum-molybdopterin complex metabolism response to metal ion molybdopterin cofactor biosynthetic process establishment of synaptic specificity at neuromuscular junction postsynaptic neurotransmitter receptor diffusion trapping Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10243 268566 Ensembl ENSG00000171723 ENSMUSG00000047454 UniProt Q9NQX3 Q8BUV3 RefSeq (mRNA) NM_001024218 NM_020806 NM_001377514 NM_001377515 NM_001377516 NM_001377517 NM_001377518 NM_001377519 NM_145965 NM_172952 RefSeq (protein) NP_001019389 NP_065857 NP_001364443 NP_001364444 NP_001364445 NP_001364446 NP_001364447 NP_001364448 NP_666077 NP_766540 Location (UCSC) Chr 14: 66.51 – 67.18 Mb Chr 12: 78.27 – 78.73 Mb PubMed search [3] [4]
Wikidata
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Gephyrin is a protein that in humans is encoded by the GPHN gene.^{[5][6][7][8][9]}

This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperekplexia and also lead to molybdenum cofactor deficiency.

Gene

Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known.^[8] The production of alternatively spliced variants is affected by noncoding regions within the gene. A ‘yin-yang’ noncoding sequence pair encompassing gephyrin has been identified.^[10] These sequences are opposites of each other - consisting of hundreds of divergent nucleotide states. Both of these patterns are uniquely human and evolved rapidly after splitting from their ancestral DNA pattern. The gephyrin yin and yang sequences are prevalent today in populations representing every major human ancestry.

Function

Gephyrin is a 93kDa multi-functional protein that is a component of the postsynaptic protein network of 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 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.^[11]

Positive antibody staining for gephyrin at a synapse is most of the time consistent with the presence of glycine and/or GABA_A receptors. Nevertheless, some exceptions can occur like in neurons of Dorsal Root Ganglions where gephyrin is absent despite the presence of GABA_A receptors.^[9] Gephyrin is considered a major scaffolding protein at inhibitory synapses, analogous in its function to that of PSD-95 at glutamatergic synapses.^[12][13] Gephyrin was identified by its interaction with the 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 GABA_A receptor.^[14]

Gephyrin displaces GABA receptors from the GABARAP/P130 complex, then brings the receptors to the synapse.^[15] Once at the synapse, the protein binds to collybistin^[16] and neuroligin 2.^[17] In cells, gephyrin appears to form oligomers of at least three subunits. Several 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.^[18]

The gephyrin protein is also required for insertion of molybdenum into molybdopterin.^[19]

As aforementioned, gephyrin also catalyzes terminal two steps of Moco biosynthesis. In the penultimate step, N-terminal G domain adenylate the apo form of the molybdopterin to form the intermediate adenylated molybdopterin. In the terminal step, the C-terminal E domain catalyzes the deadenylation and also the metal insertion mechanism.

Clinical significance

Humans with temporal lobe epilepsy have been found to have abnormally low levels of gephyrin in their temporal lobes.^[20] 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 stiff person syndrome.^[18]

Yin-yang sequences

At some point in human history, there was a DNA sequence encompassing gephyrin that split and followed two divergent evolutionary paths.^[10] These types of splits can occur when two populations become isolated from each other or when a chromosomal region does not experience recombination events. The two sequences that split from the ancestral sequence each acquired more than a hundred mutations that subsequently became common. This happened in a relatively short time on an evolutionary scale, as hundreds of mutations were fixed in distinct ‘yin’ and ‘yang’ sequences prior to human migration to Asia. It has been reported that currently Asians carry nearly equal numbers of yin and yang sequences and global populations representing every major human ancestry possess both yin and yang sequences.^[10] The existence of this massive yin-yang pattern suggests that two completely divergent evolutionary paths rapidly progressed during human history, presumably achieving the common goal of enhancing regulation of gephyrin.

Interactions

GPHN has been shown to interact with Mammalian target of rapamycin^[6] and ARHGEF9.^[16]