Identification of a gephyrin binding motif on the glycine receptor β subunit

Meyer, Guido; Kirsch, Joachim; Betz, Heinrich; Langosch, Dieter

doi:10.1016/0896-6273(95)90145-0

Cited by 392 publications

(378 citation statements)

References 41 publications

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“…Nevertheless, the functional differences reported by Ramirez-Latorre et al make in vivo receptor structure an important question. In addition to its possible effects on channel function, it is possible that the ␤3 subunit confers other properties on the receptor unrelated to channel function but more related to synaptic localization analogous to what has been observed for certain NMDA receptor (Ehlers et al, 1995;Kornau et al, 1995) and glycine receptor subunits (Meyer et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Formation of Oligomers Containing the β3 and β4 Subunits of the Rat Nicotinic Receptor

Forsayeth

Kobrin

1997

J. Neurosci.

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The role of the ␤3 and ␤4 subunits of the nicotinic acetylcholine receptor in brain is still unclear. We investigated nicotinic receptor structure with antibodies directed against unique regions of the ␤3 and ␤4 subunits of the rat nicotinic acetylcholine receptor. Anti-␤4 detected a single band of 66 kDa in most regions of the brain that was strongest in striatum and cerebellum. The 60 kDa ␤3 subunit was detected primarily in striatum and cerebellum, and faintly in hippocampus. Immunoprecipitation experiments established that the two subunits were coassembled in the cerebellum along with the ␤2 subunit. Antibodies against the ␣4, ␤2, ␤3, and ␤4 subunits immunoprecipitated ϳ75% of the bungarotoxin-insensitive nicotinic receptor from cerebellar extracts as determined by nicotine-dependent acetylcholine binding. Transfection of COS cells with cDNAs for these four subunits induced expression of a high affinity nicotinic receptor. Omission of only a single subunit from the transfection affected either the B max or the apparent K D of the receptor. Our data suggest that the ␤3 subunit functions as a structural entity that links a relatively unstable ␣4␤2 heterodimer to a more stable ␣4␤4 heterodimer. The agonistbinding site formed by ␣4␤2 has a much greater affinity than does that formed by ␣4␤4. In this respect, nicotinic receptors that contain the ␤3 subunit are structurally homologous to the muscle nicotinic receptor.Key words: nicotine; acetylcholine; receptor; antibody; ␤3; ␤4; subunit Nicotinic acetylcholine receptors (nAChR) expressed in the CNS are members of a superfamily of ligand-gated ion channels that also include the muscle-type nAChR, GABA A , glycine, and 5-HT 3 receptors (Barnard et al., 1987;Egebjerg et al., 1991;Maricq et al., 1991;Moriyoshi et al., 1991;Monyer et al., 1992). Nine different rat neuronal nAChR subunit cDNAs (␣2, ␣3, ␣4, ␣5, ␣6, ␣7, ␤2, ␤3, and ␤4) have been cloned (for review, see Sargent, 1993). Most of the receptors in the family are thought to contain two or more different subunits, but the precise combinations of these subunits that exist in vivo are largely unknown. Previous work has indicated that the major high affinity nicotinic receptor in rat brain is composed of ␣4 and ␤2 subunits (Nakayama et al., 1991;Flores et al., 1992;Marks et al., 1992). More recent evidence indicates that deletion of the ␤2 subunit gene results in the loss of high affinity nicotine-binding sites from mouse brain (Picciotto et al., 1995). Nicotinic receptors have also been reconstituted in Xenopus oocytes. Thus, the ␤2 and ␤4 subunits can combine with various ␣ subunits to form functional receptors, permitting the formation of many types of receptor with unique pharmacological characteristics (Luetje and Patrick, 1991). Much less is known about the ␤3 subunit. It does not express any channel activity in oocytes in combination with any other single subunit , nor has it been demonstrated at the protein level in the CNS. Both the ␤3 and ␤4 subunits seem, by in situ hybridization, to have a more restric...

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Section: Discussionmentioning

confidence: 99%

Formation of Oligomers Containing the β3 and β4 Subunits of the Rat Nicotinic Receptor

Forsayeth

Kobrin

1997

J. Neurosci.

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“…7 The cytoplasmic loop of the GlyR β-subunit was later shown to bind to the E domain dimerization interface of gephyrin. 49,50 Coexpression of GlyR with gephyrin was found to change the ligand-binding affinities of human embryonic kidney 293 cells. 51 Treatment of rat spinal neurons with gephyrin antisense oligonucleotides was shown to block the formation of GlyR clusters in the neuronal membrane, suggesting that gephyrin is required to anchor GlyR in postsynaptic membrane specializations.…”

Section: Glyr β-Subunitmentioning

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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“…Initial cross-linking studies using puriWed spinal cord GlyR suggested that the receptor forms a pentamer with a deduced stoichiometry of three and two subunits and that the subunit was not involved in ligand binding (Langosch et al 1988;Laube et al 2002). Through its long intracellular loop between TM3 and TM4, the subunit can bind to gephyrin (Kim et al 2006;Meyer et al 1995;Sola et al 2004), thereby enabling the formation GlyR aggregations linked to subsynaptic protein scaVolds. However, the gephyrin scaVold (see below) is believed to provide three binding sites for GlyR subunits (Schrader et al 2004).…”

Section: Postsynaptic Membrane Specializationmentioning

confidence: 99%

“…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). The known GlyR subunits and many GABA A receptors did not bind gephyrin in a cellular assay .…”

Section: Anchoring and Traycking Of Glyrmentioning

confidence: 99%

“…The central part of the GlyR subunit large cytoplasmic loop is bound in a symmetric "key and lock" fashion to each E-domain monomer in a pocket adjacent to the dimer interface (Kim et al 2006). Structure-deduced mutagenesis followed by in vitro binding and in vivo colocalization assays suggest a hydrophobic interaction between Phe 330 of the gephyrin E-domain and Phe 398 and Ile 400 of the GlyR subunit as crucial for this interaction (Kim et al 2006;Kneussel et al 1999b;Meyer et al 1995).…”

Section: Analysis Of Gephyrin Dewcient Micementioning

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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Identification of a gephyrin binding motif on the glycine receptor β subunit

Cited by 392 publications

References 41 publications

Formation of Oligomers Containing the β3 and β4 Subunits of the Rat Nicotinic Receptor

Formation of Oligomers Containing the β3 and β4 Subunits of the Rat Nicotinic Receptor

Gephyrin: a central GABAergic synapse organizer

Molecular architecture of glycinergic synapses

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