The Roles of the Dystrophin-Associated Glycoprotein Complex at the Synapse

Pilgram, Gonneke S. K.; Potikanond, Saranyapin; Baines, Richard A.; Fradkin, Lee G.; Noordermeer, Jasprina N.

doi:10.1007/s12035-009-8089-5

Cited by 128 publications

(111 citation statements)

References 186 publications

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“…As it is likely that horizontal cell lateral elements express adhesion molecules that maintain the triad architecture, loss of these proteins after horizontal cell ablation may disrupt the synapse. To date, a few glycoproteins have been identified that play structural roles in triad synapses, such as dystrophin (Pilgram et al, 2010), retinoschisin (Johnson et al, 1996), and pikachurin (Sato et al, 2008), but these proteins are synthesized by either photoreceptors or bipolar cells. However, in chick horizontal cells, N-cadherin is required for dendrite morphogenesis and subsequent synapse formation with photoreceptor cells (Tanabe et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Ablation of Retinal Horizontal Cells from Adult Mice Leads to Rod Degeneration and Remodeling in the Outer Retina

Sonntag

Dedek²,

Dorgau³

et al. 2012

Journal of Neuroscience

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In the brain, including the retina, interneurons show an enormous structural and functional diversity. Retinal horizontal cells represent a class of interneurons that form triad synapses with photoreceptors and ON bipolar cells. At this first retinal synapse, horizontal cells modulate signal transmission from photoreceptors to bipolar cells by feedback and feedforward inhibition. To test how the fully developed retina reacts to the specific loss of horizontal cells, these interneurons were specifically ablated from adult mice using the diphtheria toxin (DT)/DT-receptor system and the connexin57 promoter. Following ablation, the retinal network responded with extensive remodeling: rods retracted their axons from the outer plexiform layer and partially degenerated, whereas cones survived. Cone pedicles remained in the outer plexiform layer and preserved synaptic contacts with OFF but not with ON bipolar cells. Consistently, the retinal ON pathway was impaired, leading to reduced amplitudes and prolonged latencies in electroretinograms. However, ganglion cell responses showed only slight changes in time course, presumably because ON bipolar cells formed multiple ectopic synapses with photoreceptors, and visual performance, assessed with an optomotor system, was only mildly affected. Thus, the loss of an entire interneuron class can be largely compensated even by the adult retinal network.

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Section: Discussionmentioning

confidence: 99%

Ablation of Retinal Horizontal Cells from Adult Mice Leads to Rod Degeneration and Remodeling in the Outer Retina

Sonntag

Dedek²,

Dorgau³

et al. 2012

Journal of Neuroscience

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“…The molecular composition of the DGC differs between muscle sarcolemma, neuromuscular junction, brain and retina, and astrocytes [91,92], where, for instance, the DGC is involved in proper membrane targeting of aquaporin 4 at end-feet in contact with brain blood vessels [93,94].…”

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

Molecular and functional heterogeneity of GABAergic synapses

Fritschy

Panzanelli

Tyagarajan

2012

Cell. Mol. Life Sci.

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Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA(A) receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA(A) receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA(A) receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapses. AbstractKnowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA A receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA A receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA A receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophinglycoprotein complex to the molecular ...

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“…The cross-linking of receptors by rapsyn, therefore, seems to be sufficient to reduce receptor diffusion and, thereby, maintain an elevated receptor concentration, in agreement with recent single-molecule tracking experiments (24). It is, nonetheless, likely that interactions between rapsyn and the actin cytoskeleton via the dystroglycan complex further stabilize receptor clusters (26).…”

Section: Discussionmentioning

confidence: 99%

Structure and superorganization of acetylcholine receptor–rapsyn complexes

Zuber

Unwin

2013

Proc. Natl. Acad. Sci. U.S.A.

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The scaffolding protein at the neuromuscular junction, rapsyn, enables clustering of nicotinic acetylcholine receptors in high concentration and is critical for muscle function. Patients with insufficient receptor clustering suffer from muscle weakness. However, the detailed organization of the receptor-rapsyn network is poorly understood: it is unclear whether rapsyn first forms a wide meshwork to which receptors can subsequently dock or whether it only forms short bridges linking receptors together to make a large cluster. Furthermore, the number of rapsyn-binding sites per receptor (a heteropentamer) has been controversial. Here, we show by cryoelectron tomography and subtomogram averaging of Torpedo postsynaptic membrane that receptors are connected by up to three rapsyn bridges, the minimum number required to form a 2D network. Half of the receptors belong to rapsyn-connected groups comprising between two and fourteen receptors. Our results provide a structural basis for explaining the stability and low diffusion of receptors within clusters.cryoelectron microscopy | neurotransmitter receptor clustering | synapse | ligand-gated ion channel | tetratricopeptide repeat T he cytoplasmic protein rapsyn, also known as the 43K protein, interacts with nicotinic acetylcholine receptors in the postsynaptic membrane at the neuromuscular junction, forming clusters where receptors are present in high concentration. Such clustering is necessary for efficient neurotransmission and, hence, muscle functioning. Rapsyn-deficient mice fail to form clusters, show severe muscle weakness and breathing difficulties, and die within hours after birth (1). Furthermore, many patients suffering from congenital myasthenic syndrome are found to have mutations in rapsyn (2).Rapsyn is a 43-kDa protein containing a myristoylation site necessary for submembrane localization, seven tetratricopeptide repeats (TRPs), a putative coiled-coil domain, and a RING-H2 domain (3). Two TPRs are necessary for rapsyn self-association, whereas association with receptor depends on the predicted coiled-coil (3, 4). Rapsyn is also linked through the RING-H2 domain to dystroglycan, a protein that indirectly binds actin cytoskeleton (5). Recombinant rapsyn expressed in heterologous systems spontaneously aggregates underneath the plasma membrane (3), suggesting that rapsyn might first form a wide scaffold to which receptors can subsequently dock (6). On the other hand, rapsyn and the receptor are cotransported in membrane vesicles toward the plasma membrane, and the receptor is necessary for rapsyn clustering in C2 myotubes, raising the possibility that rapsyn only forms short bridges linking receptors together to form a large cluster (7-9). Furthermore, the number of rapsyn-binding sites per receptor (a heteropentamer) has been variously estimated to be between one and five (6, 10, 11). Therefore, the molecular details and organization of the receptor-rapsyn network are poorly understood.To address these issues, we applied cryoelectron tomography, combined with...

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The Roles of the Dystrophin-Associated Glycoprotein Complex at the Synapse

Cited by 128 publications

References 186 publications

Ablation of Retinal Horizontal Cells from Adult Mice Leads to Rod Degeneration and Remodeling in the Outer Retina

Ablation of Retinal Horizontal Cells from Adult Mice Leads to Rod Degeneration and Remodeling in the Outer Retina

Molecular and functional heterogeneity of GABAergic synapses

Structure and superorganization of acetylcholine receptor–rapsyn complexes

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