Gephyrin is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''GPHN''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
This gene encodes a neuronal assembly
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that anchors inhibitory
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
Neurotra ...
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 cytosk ...
dimers. In nonneuronal tissues, the encoded protein is also required for
molybdenum
Molybdenum is a chemical element; it has Symbol (chemistry), symbol Mo (from Neo-Latin ''molybdaenum'') and atomic number 42. The name derived from Ancient Greek ', meaning lead, since its ores were confused with lead ores. Molybdenum minerals hav ...
cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition
hyperekplexia
Hyperekplexia (; "exaggerated surprise") is a neurological disorder characterized by a pronounced startle response to tactile or acoustic stimuli and an ensuing period of hypertonia. The hypertonia may be predominantly truncal, attenuated durin ...
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 d ...
.
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
Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and regula ...
regions within the gene. There are two major, very different variants among human populations in these regulatory regions termed "yin" and "yang".
[*]
Function
Gephyrin is a 93kDa multi-functional
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
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 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.
Neuronal structure
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. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
and/or
GABAA receptors. Nevertheless, some exceptions can occur like in
neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
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 glycine receptor (abbreviated as GlyR or GLR) is the receptor
Receptor may refer to:
* Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochem ...
, 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 brain specific 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 bind ...
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, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...
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.
Moco biosynthesis
The gephyrin protein is also required for insertion of
molybdenum
Molybdenum is a chemical element; it has Symbol (chemistry), symbol Mo (from Neo-Latin ''molybdaenum'') and atomic number 42. The name derived from Ancient Greek ', meaning lead, since its ores were confused with lead ores. Molybdenum minerals hav ...
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: Molybdopte ...
. In the penultimate step, N-terminal G domain adenylate the apo form of the molybdopterin to form the intermediate adenylated molybdopterin (
molybdopterin adenylyltransferase
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: Molybdopte ...
). In the terminal step, the C-terminal E domain catalyzes the deadenylation and also the metal insertion mechanism (
molybdopterin molybdenumtransferase).
Clinical significance
Humans with
temporal lobe epilepsy
In the field of neurology, temporal lobe epilepsy is an enduring brain disorder that causes unprovoked seizures from the temporal lobe. Temporal lobe epilepsy is the most common type of focal onset epilepsy among adults. Seizure symptoms and b ...
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, is a rare neurological disorder of unclear cause characterized by progressive muscular rigidity and stiffness. The stiffness primarily affects the truncal muscles and is characterised ...
.
Yin-yang sequences

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 advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with
Mammalian target of rapamycin
The mammalian target of sirolimus, 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 ''M ...
[ 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
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
*
*
{{Metabolism of vitamins, coenzymes, and cofactors