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IUCrJ Sep 2020The cholinergic postsynaptic membrane is an acetyl-choline receptor-rich membrane mediating fast chemical communication at the nerve-muscle synapse. Here, cryo-EM is...
The cholinergic postsynaptic membrane is an acetyl-choline receptor-rich membrane mediating fast chemical communication at the nerve-muscle synapse. Here, cryo-EM is used to examine the protein-lipid architecture of this membrane in tubular vesicles obtained from the (muscle-derived) electric organ of the ray. As reported earlier, the helical arrangement of the protein component of the vesicles facilitates image averaging and enables us to determine how cholesterol and phospho-lipid molecules are distributed in the surrounding matrix, using headgroup size as a means to discriminate between the two kinds of lipid. It is shown that cholesterol segregates preferentially around the receptors in both leaflets of the lipid bilayer, interacting robustly with specific transmembrane sites and creating a network of bridging microdomains. Cholesterol interactions with the receptor are apparently essential for stabilizing and maintaining its physiological architecture, since the transmembrane structure contracts, involving displacements of the helices at the outer membrane surface by ∼2 Å (1-3 Å), when this lipid is extracted. The microdomains may promote cooperativity between neighbouring receptors, leading to an enhanced postsynaptic response.
PubMed: 32939277
DOI: 10.1107/S2052252520009446 -
Matrix Biology : Journal of the... Jan 2017The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor... (Review)
Review
The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of skeletal muscles. The synaptic cleft between these two cells is filled with basal lamina. Laminins are heterotrimer extracellular matrix molecules that are key members of the basal lamina. Laminin α4, α5, and β2 chains specifically localize to NMJs, and these laminin isoforms play a critical role in maintenance of NMJs and organization of synaptic vesicle release sites known as active zones. These individual laminin chains exert their role in organizing NMJs by binding to their receptors including integrins, dystroglycan, and voltage-gated calcium channels (VGCCs). Disruption of these laminins or the laminin-receptor interaction occurs in neuromuscular diseases including Pierson syndrome and Lambert-Eaton myasthenic syndrome (LEMS). Interventions to maintain proper level of laminins and their receptor interactions may be insightful in treating neuromuscular diseases and aging related degeneration of NMJs.
Topics: Abnormalities, Multiple; Animals; Basement Membrane; Calcium Channels; Dystroglycans; Eye Abnormalities; Gene Expression; Humans; Integrins; Lambert-Eaton Myasthenic Syndrome; Laminin; Motor Neurons; Muscle, Skeletal; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Neuromuscular Junction; Protein Binding; Pupil Disorders; Synaptic Vesicles
PubMed: 27614294
DOI: 10.1016/j.matbio.2016.08.008 -
Cell Reports Oct 2020Neuromuscular junctions (NMJs) govern efficient neuronal communication with muscle cells, relying on proper architecture of specialized postsynaptic compartments....
Neuromuscular junctions (NMJs) govern efficient neuronal communication with muscle cells, relying on proper architecture of specialized postsynaptic compartments. However, the intrinsic mechanism in muscle cells contributing to NMJ development remains unclear. In this study, we reveal that dynamin-2 (Dyn2) is involved in postsynaptic development of NMJs. Mutations of Dyn2 have been linked to human muscular disorder and centronuclear myopathy (CNM), as well as featured with muscle atrophy and defective NMJs, yet the function of Dyn2 at the postsynaptic membrane is largely unknown. We demonstrate that Dyn2 is enriched at the postsynaptic membrane and regulates NMJ development via actin remodeling. Dyn2 functions as an actin-bundling GTPase to regulate podosome turnover and cytoskeletal organization of the postsynaptic apparatus, and CNM-Dyn2 mutations display abnormal actin remodeling and electrophysiological activity of fly NMJs. Altogether, Dyn2 primarily regulates actin cytoskeleton remodeling and NMJ morphogenesis at the postsynaptic membrane, which is distinct from its endocytosis regulatory role at the presynaptic membrane.
Topics: Cytoskeleton; Dynamin II; Humans; Neuromuscular Junction
PubMed: 33113375
DOI: 10.1016/j.celrep.2020.108310 -
Philosophical Transactions of the Royal... Jul 2024Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand...
Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand better the possible impact of either LTP form, we explored a realistic model of a CA1 pyramidal cell equipped with known membrane mechanisms and multiple, stochastic excitatory axo-spinous synapses. Our simulations were designed to establish an input-output transfer function, the dependence between the frequency of presynaptic action potentials triggering probabilistic synaptic discharges and the average frequency of postsynaptic spiking. We found that, within the typical physiological range, potentiation of the postsynaptic current results in a greater overall output than an equivalent increase in presynaptic release probability. This difference grows stronger at lower input frequencies and lower release probabilities. Simulations with a non-hierarchical circular network of principal neurons indicated that equal increases in either synaptic fidelity or synaptic strength of individual connections also produce distinct changes in network activity, although the network phenomenology is likely to be complex. These observations should help to interpret the machinery of LTP phenomena documented . This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Long-Term Potentiation; Models, Neurological; Synapses; Pyramidal Cells; Animals; Computer Simulation; Action Potentials; CA1 Region, Hippocampal
PubMed: 38853561
DOI: 10.1098/rstb.2023.0235 -
Journal of Pharmacological Sciences Jan 2015Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug... (Review)
Review
Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.
Topics: Animals; Endoplasmic Reticulum; Humans; Mitochondria; Models, Biological; Molecular Chaperones; Psychotropic Drugs; Receptors, sigma; Signal Transduction; Sigma-1 Receptor
PubMed: 25704011
DOI: 10.1016/j.jphs.2014.07.001 -
Neuroscience Jul 2020To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the... (Review)
Review
To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the postsynaptic protein gephyrin self-assembles to form a scaffold that anchors glycine and GABARs to the cytoskeleton, thus ensuring the accurate accumulation of postsynaptic receptors at the right place. This protein undergoes several post-translational modifications which control protein-protein interaction and downstream signaling pathways. In addition, through the constant exchange of scaffolding elements and receptors in and out of synapses, gephyrin dynamically regulates synaptic strength and plasticity. The aim of the present review is to highlight recent findings on the functional role of gephyrin at GABAergic inhibitory synapses. We will discuss different approaches used to interfere with gephyrin in order to unveil its function. In addition, we will focus on the impact of gephyrin structure and distribution at the nanoscale level on the functional properties of inhibitory synapses as well as the implications of this scaffold protein in synaptic plasticity processes. Finally, we will emphasize how gephyrin genetic mutations or alterations in protein expression levels are implicated in several neuropathological disorders, including autism spectrum disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all associated with severe deficits of GABAergic signaling. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
Topics: Carrier Proteins; Humans; Membrane Proteins; Receptors, GABA-A; Synapses
PubMed: 31356900
DOI: 10.1016/j.neuroscience.2019.07.036 -
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 -
Biochimica Et Biophysica Acta Oct 2014The development of dendritic spines with specific geometry and membrane composition is critical for proper synaptic function. Specific spine membrane architecture,... (Review)
Review
The development of dendritic spines with specific geometry and membrane composition is critical for proper synaptic function. Specific spine membrane architecture, sub-spine microdomains and spine head and neck geometry allow for well-coordinated and compartmentalized signaling, disruption of which could lead to various neurological diseases. Research from neuronal cell culture, brain slices and direct in vivo imaging indicates that dendritic spine development is a dynamic process which includes transition from small dendritic filopodia through a series of structural refinements to elaborate spines of various morphologies. Despite intensive research, the precise coordination of this morphological transition, the changes in molecular composition, and the relation of spines of various morphologies to function remain a central enigma in the development of functional neuronal circuits. Here, we review research so far and aim to provide insight into the key events that drive structural change during transition from immature filopodia to fully functional spines and the relevance of spine geometry to function.
Topics: Animals; Dendritic Spines; Humans; Membrane Microdomains; Nervous System Diseases; Pseudopodia; Signal Transduction
PubMed: 24915021
DOI: 10.1016/j.bbamem.2014.06.002 -
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 Tourette´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 -
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