Diversity and phylogeny of gephyrin: Tissue-specific splice variants, gene structure, and sequence similarities to molybdenum cofactor-synthesizing and cytoskeleton-associated proteins

Ramming, Markus; Kins, Stefan; Werner, Nikos; Hermann, Achim; Betz, Heinrich; Kirsch, Joachim

doi:10.1073/pnas.97.18.10266

Cited by 78 publications

(109 citation statements)

References 38 publications

(60 reference statements)

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“…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%

“…In this context (Kneussel and Betz 2000) suggested that the then newly discovered guanine exchange factor collybistin might play an important role in this process. Collybistin, named after the Greek word for "money exchanger", had been identiWed as gephyrin-binding guanine exchange factor for monomeric GTPases of the Rho-family, which is exclusively expressed in neurons (Kins et al 2000). The hallmark of this class of exchange factors is the occurrence of a tandemdomain composed of a dbl-homology (DH) and a pleckstrin homology (PH) domain.…”

Section: Synapse Formation and Plasticitymentioning

confidence: 99%

“…Gephyrin-binding occurs in small region between the SH3-and DH domains (Grosskreutz et al 2001). Upon heterologous expression of gephyrin and collybistin in mammalian cells, both proteins accumulate in punctate membrane patches near the cell membrane (Kins et al 2000). The morphology of the gephyrin-and collybistinrich membrane patches is reminiscent of postsynaptic gephyrin aggregates, moreover these microdomains were shown to accumulate GlyRs (Kins et al 2000).…”

Section: Synapse Formation and Plasticitymentioning

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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Section: Splice Variants Expression and Distributionmentioning

confidence: 99%

Section: Synapse Formation and Plasticitymentioning

confidence: 99%

Section: Synapse Formation and Plasticitymentioning

confidence: 99%

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Molecular architecture of glycinergic synapses

Dresbach

Nawrotzki

Kremer

et al. 2008

Histochem Cell Biol

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“…10,26 Intriguingly, a high diversity of gephyrin transcripts was observed in the skeletal muscle, heart, liver and brain, all of which showed distinct patterns. This observation is in accord with the notion that gephyrin has an important role in both synaptic and metabolic pathways in the nervous system.…”

Section: Expression and Localizationmentioning

confidence: 99%

“…26 For example, gephyrin transcripts containing the C2 cassette (corresponding to exon 3) were abundantly expressed at synapses, whereas those containing the C3 and C4 cassettes (corresponding to exon 11) were not; 27 see also Fritschy et al 8 for revised gephyrin splicing cassette nomenclature.…”

Section: Expression and Localizationmentioning

confidence: 99%

Gephyrin: a central GABAergic synapse organizer

Choii

2015

Exp Mol Med

125

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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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GABA _A Receptors

Ernst¹,

Steudle²,

Bampali³

2018

Encyclopedia of Life Sciences

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GABA A (gamma‐aminobutyric acid) receptors are fast‐acting, ligand‐gated anion channels that are the major mediators of inhibitory neurotransmission in the mammalian central nervous system as well as essential elements in many nonneuronal cells. A large number of receptor subtypes arise from many subunit classes and isoforms and their respective splice variants. They share many structural and functional attributes with the other members of the pentameric ligand‐gated ion channel superfamily. At this time, the precise number and structures of native receptor subtypes are still not known. GABA A receptor subtype activity is additionally regulated by phosphorylation as well as being modulated allosterically by a variety of small molecules including benzodiazepines, chemically very diverse plant compounds, endogenous and synthetic neuroactive steroids and many more. Genetic or adaptive alterations in subunit primary structures, expression or receptor function have been implicated in many phenotypes. Key Concepts Nineteen mammalian GABR genes and their splice isoforms encode GABA A receptor subunits that are assembled into glycosylated homo or heteropentameric GABA‐gated anion channels, constituting the largest family of mammalian ligand‐gated ion channels. Expression of GABR genes is tightly regulated during development, uniquely different for individual cell types and modulated by internal and environmental stimuli ranging from hormonal status to factors such as temperature, stress or many medications. Genetic findings imply altered GABA A receptor signalling to be a contributing factor to many different phenotypes including diverse epilepsies, addiction risks and many more. GABA A receptor subunits share a common domain organisation with all other members of the pentameric ligand‐gated ion channel superfamily comprising a large extracellular domain, a transmembrane domain of four transmembrane helices (M1–M4) and an intracellular domain that is highly variable and contains a multitude of regulatory and protein–protein interaction sites. On each pentamer, depending on its subunit composition, one to five agonist binding sites and many allosteric binding sites exist that impart on each GABA A receptor subtype a uniquely distinct pharmacological profile. The transient kinetic properties of GABA A receptors depend on the subunit composition, absence or presence of allosteric modulators such as neuroactive steroids and the phosphorylation state of the individual subunits. Synaptic GABA A receptors are clustered at the postsynaptic membrane and mediate phasic inhibition, namely a fast response to presynaptic GABA release. Extrasynaptic GABA A receptors that are located away from synapses mediate tonic inhibition and are continuously activated by varying low concentrations of GABA, and thus regulating neuronal excitability.

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Diversity and phylogeny of gephyrin: Tissue-specific splice variants, gene structure, and sequence similarities to molybdenum cofactor-synthesizing and cytoskeleton-associated proteins

Abstract: glycine receptor ͉ ␥-aminobutyric acid type A receptor ͉ receptor clustering ͉ tubulin binding ͉ evolution

Cited by 78 publications

References 38 publications

Molecular architecture of glycinergic synapses

Molecular architecture of glycinergic synapses

Gephyrin: a central GABAergic synapse organizer

GABA _A Receptors

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Diversity and phylogeny of gephyrin: Tissue-specific splice variants, gene structure, and sequence similarities to molybdenum cofactor-synthesizing and cytoskeleton-associated proteins

Abstract: glycine receptor ͉ ␥-aminobutyric acid type A receptor ͉ receptor clustering ͉ tubulin binding ͉ evolution

Cited by 78 publications

References 38 publications

Molecular architecture of glycinergic synapses

Molecular architecture of glycinergic synapses

Gephyrin: a central GABAergic synapse organizer

GABA A Receptors

Contact Info

Product

Resources

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GABA _A Receptors