Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein

Prior, Peter; Schmitt, Bertram; Grenningloh, Gabriele; Pribilla, I.; Multhaup, Gerd; Beyreuther, Konrad; Maulet, Yves; Werner, Pia; Langosch, Dieter; Kirsch, Joachim; Betz, Heinrich

doi:10.1016/0896-6273(92)90136-2

Cited by 308 publications

(299 citation statements)

References 35 publications

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“…The gephyrin transcript is subject to extensive alternative splicing 10,19,20 in all three domains. Each domain contains at least three variable expression cassettes, providing a regulatory mechanism through which the signaling properties of specific synapses may be altered.…”

Section: Introductionmentioning

confidence: 99%

Gephyrin: a central GABAergic synapse organizer

2015

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Gephyrin is a central element that anchors, clusters and stabilizes glycine and γ-aminobutyric acid type A receptors at inhibitory synapses of the mammalian brain. It self-assembles into a hexagonal lattice and interacts with various inhibitory synaptic proteins. Intriguingly, the clustering of gephyrin, which is regulated by multiple posttranslational modifications, is critical for inhibitory synapse formation and function. In this review, we summarize the basic properties of gephyrin and describe recent findings regarding its roles in inhibitory synapse formation, function and plasticity. We will also discuss the implications for the pathophysiology of brain disorders and raise the remaining open questions in this field.

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Section: Introductionmentioning

confidence: 99%

Gephyrin: a central GABAergic synapse organizer

2015

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“…The 93 kDa protein was demonstrated to bind polymerized tubulin with similar aYnity and stoichiometry as microtubule-associated protein 2 (Kirsch et al 1991). It was hypothesized that this protein could form a bridge between the GlyR and the underlying microtubular cytoskeleton and therefore named gephyrin ( ; Greek: bridge) upon elucidation of its primary structure (Prior et al 1992). Gephyrin can interact with a short sequence motif (18 amino acids) within the large cytoplasmic loop of the GlyR subunit thereby establishing a direct, continuous molecular link between hetero-oligomeric GlyRs and gephyrin Kneussel et al 1999b;Meyer et al 1995).…”

Section: Anchoring and Traycking Of Glyrmentioning

confidence: 99%

“…Three splice variants of gephyrin cDNAs were identiWed (originally named P1-P3), which diVer by the insertion of polypeptide cassettes due to alternative splicing of the premRNA and additional splice variants were identiWed later on Meier et al 2000;Prior et al 1992;Ramming et al 2000). In the meantime, the nomenclature of gephyrin splice cassettes has been revised at a recent meeting exclusively devoted to the biology of gephyrin .…”

Section: Splice Variants Expression and Distributionmentioning

confidence: 99%

“…Moreover, gephyrin containing the C5 cassette has been shown to be unable to catalyze the Wnal step in molybdenum cofactor (see below) biosynthesis in vitro (Smolinsky et al 2008), indicating that alternative splicing may change diVerent properties of gephyrin in a given cellular context. Unexpectedly, Northern blots revealed, that gephyrin mRNAs are expressed in many organs except those of the lymphatic system (Prior et al 1992). In brain and spinal cord, gephyrin expression is restricted to grey matter (Kirsch et al 1993a).…”

Section: Splice Variants Expression and Distributionmentioning

confidence: 99%

“…Surprisingly, the analysis of gephyrin's primary structure revealed signiWcant sequence homologies of the amino-and carboxy-terminal thirds to proteins involved in the biosynthesis of the molybdenum cofactor (moco) (Prior et al 1992;Stallmeyer et al 1999), a pterin cofactor required for the activity of molybdenum-dependent oxidoreductases, namely sulWte oxidase, xanthine dehydrogenase and aldehyde oxidase all of which are predominantly expressed in liver but also in brain (Mendel and Schwarz 2002;Schwarz and Mendel 2006). The amino terminal part of gephyrin (amino acids 1-181), now called the G-domain, shows homologies to the MogA protein, whereas the carboxy terminal part (amino acids 318-736), now called E-domain, is homologous to the MoeA protein of E. coli.…”

Section: Homologous Proteinsmentioning

confidence: 99%

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Molecular architecture of glycinergic synapses

Dresbach

Nawrotzki

Kremer

et al. 2008

Histochem Cell Biol

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Synapses can be considered chemical machines, which are optimized for fast and repeated exocytosis of neurotransmitters from presynaptic nerve terminals and the reliable electrical or chemical transduction of neurotransmitter binding to the appropriate receptors in the postsynaptic membrane. Therefore, synapses share a common repertoire of proteins like, e.g., the release machinery and certain cell adhesion molecules. This basic repertoire must be extended in order to generate speciWcity of neurotransmission and allow plastic changes, which are considered the basis of developmental and/or learning processes. Here, we focus on these complementary molecules located in the presynaptic terminal and postsynaptic membrane specializations of glycinergic synapses. Moreover, as speciWcity of neurotransmission in this system is established by the speciWc binding of the neurotransmitter to its receptor, we review the molecular properties of glycine receptor subunits and their assembly into functional glycine receptors with diVerent functional characteristics. The past years have revealed that the molecular machinery underlying inhibitory and especially glycinergic postsynaptic membrane specializations is more complex and dynamic than previously anticipated from morphological studies. The emerging features include structural components as well as signaling modules, which could confer the plasticity required for the proper function of distinct motor and sensory functions.

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Gephyrin accumulates at specific plasmalemma loci during neuronal maturation in vitro

1996

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The distribution of glycine receptor (GlyR)-associated gephyrin has been investigated in rat spinal cord neurons maintained in vitro by means of immunocytochemical techniques. Gephyrin, which is crucial for the stabilization of postsynaptic GlyR microdomains, is present in mature neurons at postsynaptic differentiations. With immunofluorescence, discontinuous patches of gephyrin were detected within the neuronal soma of spinal cord neurons on the 1st day after plating. Subsequently, gephyrin was present at membrane areas that correspond to points of contact between cells or with the culture dish. By the 5th day, gephrin was mostly associated with the MAP2-positive somatodendritic compartment. With immunoelectron microscopy, gephyrin blobs detected at the earliest stages (1-3 days after plating) were found within the cytoplasm or associated with the plasma membrane. Asymmetrically immunostained intercellular contacts were only detected after 5 days, and gephyrin was found in association with clearly differentiated postsynaptic membranes at 7 days. At later stages, we observed gephyrin immunoreactivity only at some synapses. Our results suggest that gephyrin accumulates initially at the locus of cell-to-cell contacts involved in adhesion processes. These localizations may define hot spots for later accumulation of the GlyR and possibly other receptors.

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Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein

Cited by 308 publications

References 35 publications

Gephyrin: a central GABAergic synapse organizer

Gephyrin: a central GABAergic synapse organizer

Molecular architecture of glycinergic synapses

Gephyrin accumulates at specific plasmalemma loci during neuronal maturation in vitro

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