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Annals of the New York Academy of... Jan 2018While the majority of myasthenia gravis patients express antibodies targeting the acetylcholine receptor, the second most common cohort instead displays autoantibodies... (Review)
Review
While the majority of myasthenia gravis patients express antibodies targeting the acetylcholine receptor, the second most common cohort instead displays autoantibodies against muscle-specific kinase (MuSK). MuSK is a transmembrane tyrosine kinase found in the postsynaptic membrane of the neuromuscular junction. During development, MuSK serves as a signaling hub, coordinating the alignment of the pre- and postsynaptic components of the synapse. Adult mice that received repeated daily injections of IgG from anti-MuSK myasthenia gravis patients developed muscle weakness, associated with neuromuscular transmission failure. MuSK autoantibodies are predominantly of the IgG4 type. They suppress the kinase activity of MuSK and the phosphorylation of target proteins in the postsynaptic membrane. Loss of postsynaptic acetylcholine receptors is the primary cause of neuromuscular transmission failure. MuSK autoantibodies also disrupt the capacity of the motor nerve terminal to adaptively increase acetylcholine release in response to the reduced postsynaptic responsiveness to acetylcholine. The passive IgG transfer model of MuSK myasthenia gravis has been used to test candidate treatments. Pyridostigmine, a first-line cholinesterase inhibitor drug, exacerbated the disease process, while 3,4-diaminopyridine and albuterol were found to be beneficial in this mouse model.
Topics: Animals; Cholinesterase Inhibitors; Female; Humans; Immunization, Passive; Mice; Muscle Proteins; Myasthenia Gravis, Autoimmune, Experimental; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic; Synapses
PubMed: 29125188
DOI: 10.1111/nyas.13513 -
Molecular Brain Sep 2017The neurotransmitter glutamate facilitates neuronal signalling at excitatory synapses. Glutamate is released from the presynaptic membrane into the synaptic cleft.... (Review)
Review
The neurotransmitter glutamate facilitates neuronal signalling at excitatory synapses. Glutamate is released from the presynaptic membrane into the synaptic cleft. Across the synaptic cleft glutamate binds to both ion channels and metabotropic glutamate receptors at the postsynapse, which expedite downstream signalling in the neuron. The postsynaptic density, a highly specialized matrix, which is attached to the postsynaptic membrane, controls this downstream signalling. The postsynaptic density also resets the synapse after each synaptic firing. It is composed of numerous proteins including a family of Discs large associated protein 1, 2, 3 and 4 (DLGAP1-4) that act as scaffold proteins in the postsynaptic density. They link the glutamate receptors in the postsynaptic membrane to other glutamate receptors, to signalling proteins and to components of the cytoskeleton. With the central localisation in the postsynapse, the DLGAP family seems to play a vital role in synaptic scaling by regulating the turnover of both ionotropic and metabotropic glutamate receptors in response to synaptic activity. DLGAP family has been directly linked to a variety of psychological and neurological disorders. In this review we focus on the direct and indirect role of DLGAP family on schizophrenia as well as other brain diseases.
Topics: Amino Acid Sequence; Animals; Brain; Brain Diseases; Humans; Models, Biological; Neurons; Protein Interaction Mapping; SAP90-PSD95 Associated Proteins
PubMed: 28870203
DOI: 10.1186/s13041-017-0324-9 -
Developmental Neurobiology Jul 2021In excitable membranes, the clustering of voltage-gated sodium channels (VGSC) serves to enhance excitability at critical sites. The two most profoundly studied sites of... (Review)
Review
In excitable membranes, the clustering of voltage-gated sodium channels (VGSC) serves to enhance excitability at critical sites. The two most profoundly studied sites of channel clustering are the axon initial segment, where action potentials are generated and the node of Ranvier, where action potentials propagate along myelinated axons. The clustering of VGSC is found, however, in other highly excitable sites such as axonal terminals, postsynaptic membranes of dendrites and muscle fibers, and pre-myelinated axons. In this review, different examples of axonal as well as non-axonal clustering of VGSC are discussed and the underlying mechanisms are compared. Whether the clustering of channels is intrinsically or extrinsically induced, it depends on the submembranous actin-based cytoskeleton that organizes these highly specialized membrane microdomains through specific adaptor proteins.
Topics: Action Potentials; Axons; Cluster Analysis; Voltage-Gated Sodium Channels
PubMed: 31859465
DOI: 10.1002/dneu.22728 -
Pharmacological Research May 2023Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are widely distributed both pre- and post-synaptically in the mammalian brain. By...
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are widely distributed both pre- and post-synaptically in the mammalian brain. By modulating cation flux across cell membranes, neuronal nAChRs regulate neuronal excitability and the release of a variety of neurotransmitters to influence multiple physiologic and behavioral processes including synaptic plasticity, motor function, attention, learning and memory. Abnormalities of neuronal nAChRs have been implicated in the pathophysiology of neurologic disorders including Alzheimer's disease, Parkinson's disease, epilepsy, and TouretteĀ“s syndrome, as well as psychiatric disorders including schizophrenia, depression, and anxiety. The potential role of nAChRs in a particular illness may be indicated by alterations in the expression of nAChRs in relevant brain regions, genetic variability in the genes encoding for nAChR subunit proteins, and/or clinical or preclinical observations where specific ligands showed a therapeutic effect. Over the past 25 years, extensive preclinical and some early clinical evidence suggested that ligands at nAChRs might have therapeutic potential for neurologic and psychiatric disorders. However, to date the only approved indications for nAChR ligands are smoking cessation and the treatment of dry eye disease. It has been argued that progress in nAChR drug discovery has been limited by translational gaps between the preclinical models and the human disease as well as unresolved questions regarding the pharmacological goal (i.e., agonism, antagonism or receptor desensitization) depending on the disease.
Topics: Animals; Humans; Receptors, Nicotinic; Ligands; Mental Disorders; Brain; Schizophrenia; Mammals
PubMed: 37044234
DOI: 10.1016/j.phrs.2023.106764 -
Histochemistry and Cell Biology Nov 2018Scaffolding proteins underlying postsynaptic membrane specializations are important structural and functional components of both excitatory and inhibitory synapses. At... (Review)
Review
Scaffolding proteins underlying postsynaptic membrane specializations are important structural and functional components of both excitatory and inhibitory synapses. At inhibitory synapses, gephyrin was identified as anchoring protein. Gephyrin self-assembles into a complex flat submembranous lattice that slows the lateral mobility of glycine and GABA receptors, thus allowing for their clustering at postsynaptic sites. The structure and stability of the gephyrin lattice is dynamically regulated by posttranslational modifications and interactions with binding partners. As gephyrin is the core scaffolding protein for virtually all inhibitory synapses, any changes in the structure or stability of its lattice can profoundly change the packing density of inhibitory receptors and, therefore, alter inhibitory drive. Intriguingly, gephyrin plays a completely independent role in non-neuronal cells, where it facilitates two steps in the biosynthesis of the molybdenum cofactor. In this review, we provide an overview of the role of gephyrin at inhibitory synapses and beyond. We discuss its dynamic regulation, the nanoscale architecture of its synaptic lattice, and the implications of gephyrin dysfunction for neuropathologic conditions, such as Alzheimer's disease and epilepsy.
Topics: Animals; Carrier Proteins; Humans; Membrane Proteins; Synapses
PubMed: 30264265
DOI: 10.1007/s00418-018-1725-2 -
Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction.Frontiers in Neurology 2022The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the... (Review)
Review
The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as "synaptopathy." Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches.
PubMed: 35350397
DOI: 10.3389/fneur.2022.826211 -
Cell Reports Mar 2023Synaptotagmin III (Syt3) is a Ca-dependent membrane-traffic protein that is highly concentrated in synaptic plasma membranes and affects synaptic plasticity by...
Synaptotagmin III (Syt3) is a Ca-dependent membrane-traffic protein that is highly concentrated in synaptic plasma membranes and affects synaptic plasticity by regulating post-synaptic receptor endocytosis. Here, we show that Syt3 is upregulated in the penumbra after ischemia/reperfusion (I/R) injury. Knockdown of Syt3 protects against I/R injury, promotes recovery of motor function, and inhibits cognitive decline. Overexpression of Syt3 exerts the opposite effects. Mechanistically, I/R injury augments Syt3-GluA2 interactions, decreases GluA2 surface expression, and promotes the formation of Ca-permeable AMPA receptors (CP-AMPARs). Using a CP-AMPAR antagonist or dissociating the Syt3-GluA2 complex via TAT-GluA2-3Y peptide promotes recovery from neurological impairments and improves cognitive function. Furthermore, Syt3 knockout mice are resistant to cerebral ischemia because they show high-level expression of surface GluA2 and low-level expression of CP-AMPARs after I/R. Our results indicate that Syt3-GluA2 interactions, which regulate the formation of CP-AMPARs, may be a therapeutic target for ischemic insults.
Topics: Animals; Mice; Brain; Carrier Proteins; Membrane Proteins; Neuronal Plasticity; Stroke; Synaptotagmins
PubMed: 36892998
DOI: 10.1016/j.celrep.2023.112233 -
Acta Crystallographica. Section D,... Dec 2018This article reviews recent work in applying neutron and X-ray scattering towards the elucidation of the molecular mechanisms of volatile anesthetics. Experimental... (Review)
Review
This article reviews recent work in applying neutron and X-ray scattering towards the elucidation of the molecular mechanisms of volatile anesthetics. Experimental results on domain mixing in ternary lipid mixtures, and the influence of volatile anesthetics and hydrostatic pressure are placed in the contexts of ion-channel function and receptor trafficking at the postsynaptic density.
Topics: Anesthetics; Animals; Humans; Hydrostatic Pressure; Ion Channels; Membrane Lipids; Membrane Microdomains; Membrane Proteins; Neuronal Plasticity; Neutron Diffraction; Post-Synaptic Density; Receptors, Cell Surface; Scattering, Small Angle; Volatile Organic Compounds; X-Ray Diffraction
PubMed: 30605131
DOI: 10.1107/S2059798318004771 -
Molecular Cell Jan 2024Membraneless organelles formed by phase separation of proteins and nucleic acids play diverse cellular functions. Whether and, if yes, how membraneless organelles in...
Membraneless organelles formed by phase separation of proteins and nucleic acids play diverse cellular functions. Whether and, if yes, how membraneless organelles in ways analogous to membrane-based organelles also undergo regulated fusion and fission is unknown. Here, using a partially reconstituted mammalian postsynaptic density (PSD) condensate as a paradigm, we show that membraneless organelles can undergo phosphorylation-dependent fusion and fission. Without phosphorylation of the SAPAP guanylate kinase domain-binding repeats, the upper and lower layers of PSD protein mixtures form two immiscible sub-compartments in a phase-in-phase organization. Phosphorylation of SAPAP leads to fusion of the two sub-compartments into one condensate accompanied with an increased Stargazin density in the condensate. Dephosphorylation of SAPAP can reverse this event. Preventing SAPAP phosphorylation inĀ vivo leads to increased separation of proteins from the lower and upper layers of PSD sub-compartments. Thus, analogous to membrane-based organelles, membraneless organelles can also undergo regulated fusion and fission.
Topics: Animals; Biomolecular Condensates; Phosphorylation; Post-Synaptic Density; Cell Physiological Phenomena; Protein Binding; Organelles; Mammals
PubMed: 38096828
DOI: 10.1016/j.molcel.2023.11.011 -
International Journal of Molecular... Oct 2017The commands that control animal movement are transmitted from motor neurons to their target muscle cells at the neuromuscular junctions (NMJs). The NMJs contain many... (Review)
Review
The commands that control animal movement are transmitted from motor neurons to their target muscle cells at the neuromuscular junctions (NMJs). The NMJs contain many protein species whose role in transmission depends not only on their inherent properties, but also on how they are distributed within the complex structure of the motor nerve terminal and the postsynaptic muscle membrane. These molecules mediate evoked chemical transmitter release from the nerve and the action of that transmitter on the muscle. Human NMJs are among the smallest known and release the smallest number of transmitter "quanta". By contrast, they have the most deeply infolded postsynaptic membranes, which help to amplify transmitter action. The same structural features that distinguish human NMJs make them particularly susceptible to pathological processes. While much has been learned about the molecules which mediate transmitter release and action, little is known about the molecular processes that control the growth of the cellular and subcellular components of the NMJ so as to give rise to its mature form. A major challenge for molecular biologists is to understand the molecular basis for the development and maintenance of functionally important aspects of NMJ structure, and thereby to point to new directions for treatment of diseases in which neuromuscular transmission is impaired.
Topics: Evolution, Molecular; Humans; Neuromuscular Junction; Synaptic Transmission
PubMed: 29048368
DOI: 10.3390/ijms18102183