Gephyrin is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''GPHN''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
This gene encodes a neuronal assembly
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that anchors inhibitory
neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and
tubulin
Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
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
Hyperekplexia (; "exaggerated surprise") is a very rare neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia. The hypertonia may be predominantly truncal, attenuated during ...
and also lead to
molybdenum cofactor deficiency
Molybdenum cofactor deficiency is a rare human disease in which the absence of molybdopterin – and consequently its molybdenum complex, commonly called molybdenum cofactor – leads to accumulation of toxic levels of sulphite and neurological da ...
.
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.
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.
[*] 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
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that is a component of the postsynaptic protein network of
inhibitory synapse
An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...
s. 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
Small-angle X-ray scattering (SAXS) is a small-angle scattering technique by which nanoscale density differences in a sample can be quantified. This means that it can determine nanoparticle size distributions, resolve the size and shape of (monodi ...
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
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
and/or
GABAA receptors. Nevertheless, some exceptions can occur like in
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s 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
PSD-95
PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene.
PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
at
glutamatergic synapses.
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.
Gephyrin displaces GABA receptors from the
GABARAP
Gamma-aminobutyric acid receptor-associated protein is a protein that in humans is encoded by the ''GABARAP'' gene.
Function
Gamma-aminobutyric acid A receptors ABA(A) receptorsare ligand-gated chloride channels that mediate inhibitory neurot ...
/
P130 complex, then brings the receptors to the synapse.
Once at the synapse, the protein binds to
collybistin
Collybistin is a protein identified as a regulator of the localization of gephyrin, inducing the formation of submembrane gephyrin aggregates that accumulate glycine and GABA receptors. In 2000 it was identified as a gephyrin binding partner, an ...
and
neuroligin 2.
In cells, gephyrin appears to form
oligomers
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
of at least three subunits. Several
splice variant
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...
s 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 for insertion of
molybdenum into
molybdopterin
Molybdopterins are a class of cofactors found in most molybdenum-containing and all tungsten-containing enzymes. Synonyms for molybdopterin are: MPT and pyranopterin-dithiolate. The nomenclature for this biomolecule can be confusing: Molybdopteri ...
.
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
Temporal lobe epilepsy (TLE) is a chronic disorder of the nervous system which is characterized by recurrent, unprovoked focal seizures that originate in the temporal lobe of the brain and last about one or two minutes. TLE is the most common ...
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
stiff person syndrome
Stiff-person syndrome (SPS), also known as stiff-man syndrome (SMS), is a rare neurologic disorder of unclear cause characterized by progressive rigidity and stiffness. The stiffness primarily affects the truncal muscles and is superimposed by s ...
.
Yin-yang sequences
![Yin-yang DNA sequences encompassing human gephyrin gene](https://upload.wikimedia.org/wikipedia/commons/3/35/Yin-yang_DNA_sequences_encompassing_human_gephyrin_gene.jpg)
At some point in human history, there was a DNA sequence encompassing ''gephyrin'' that split and followed two divergent evolutionary paths.
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.
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
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
Mammalian target of rapamycin
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
[ and ]ARHGEF9
Rho guanine nucleotide exchange factor 9 is a protein that in humans is encoded by the ''ARHGEF9'' gene.
Function
ARHGEF9 belongs to a family of Rho-like GTPases that act as molecular switches by cycling from the active GTP-bound state to the ...
.
References
Further reading
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External links
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{{Metabolism of vitamins, coenzymes, and cofactors