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Proceedings of the National Academy of... Oct 2021Recent work has highlighted roles for thermodynamic phase behavior in diverse cellular processes. Proteins and nucleic acids can phase separate into three-dimensional...
Recent work has highlighted roles for thermodynamic phase behavior in diverse cellular processes. Proteins and nucleic acids can phase separate into three-dimensional liquid droplets in the cytoplasm and nucleus and the plasma membrane of animal cells appears tuned close to a two-dimensional liquid-liquid critical point. In some examples, cytoplasmic proteins aggregate at plasma membrane domains, forming structures such as the postsynaptic density and diverse signaling clusters. Here we examine the physics of these surface densities, employing minimal simulations of polymers prone to phase separation coupled to an Ising membrane surface in conjunction with a complementary Landau theory. We argue that these surface densities are a phase reminiscent of prewetting, in which a molecularly thin three-dimensional liquid forms on a usually solid surface. However, in surface densities the solid surface is replaced by a membrane with an independent propensity to phase separate. We show that proximity to criticality in the membrane dramatically increases the parameter regime in which a prewetting-like transition occurs, leading to a broad region where coexisting surface phases can form even when a bulk phase is unstable. Our simulations naturally exhibit three-surface phase coexistence even though both the membrane and the polymer bulk only display two-phase coexistence on their own. We argue that the physics of these surface densities may be shared with diverse functional structures seen in eukaryotic cells.
Topics: Animals; Cell Membrane; Cytoplasm; Polymers; Post-Synaptic Density; Proteins; Thermodynamics
PubMed: 34599097
DOI: 10.1073/pnas.2103401118 -
Traffic (Copenhagen, Denmark) Nov 2019Bonafide claudin proteins are functional and structural components of tight junctions and are largely responsible for barrier formation across epithelial and endothelial... (Review)
Review
Bonafide claudin proteins are functional and structural components of tight junctions and are largely responsible for barrier formation across epithelial and endothelial membranes. However, current advances in the understanding of claudin biology have revealed their unexpected functions in the brain. Apart from maintaining blood-brain barriers in the brain, other functions of claudins in neurons and at synapses have been largely elusive and are just coming to light. In this review, we summarize the functions of claudins in the brain and their association in neuronal diseases. Further, we go on to cover some recent studies that show that claudins play signaling functions in neurons by regulating trafficking of postsynaptic receptors and controlling dendritic morphogenesis in the model organism Caenorhabditis elegans.
Topics: Animals; Brain; Claudins; Humans; Nervous System Diseases; Neurons
PubMed: 31418988
DOI: 10.1111/tra.12685 -
British Journal of Pharmacology Feb 2020Histamine, acting via distinct histamine H , H , H , and H receptors, regulates various physiological and pathological processes, including pain. In the last two... (Review)
Review
Histamine, acting via distinct histamine H , H , H , and H receptors, regulates various physiological and pathological processes, including pain. In the last two decades, there has been a particular increase in evidence to support the involvement of H receptor and H receptor in the modulation of neuropathic pain, which remains challenging in terms of management. However, recent data show contrasting effects on neuropathic pain due to multiple factors that determine the pharmacological responses of histamine receptors and their underlying signal transduction properties (e.g., localization on either the presynaptic or postsynaptic neuronal membranes). This review summarizes the most recent findings on the role of histamine and the effects mediated by the four histamine receptors in response to the various stimuli associated with and promoting neuropathic pain. We particularly focus on mechanisms underlying histamine-mediated analgesia, as we aim to clarify the analgesic potential of histamine receptor ligands in neuropathic pain. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.
Topics: Analgesics; Histamine; Humans; Neuralgia; Pain Management; Receptors, Histamine
PubMed: 31046146
DOI: 10.1111/bph.14696 -
Cell Reports Nov 2023Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter...
Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABA receptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABA receptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABA receptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.
Topics: Receptors, GABA-A; Synapses; Carrier Proteins; Receptors, Neurotransmitter; gamma-Aminobutyric Acid
PubMed: 37910506
DOI: 10.1016/j.celrep.2023.113331 -
Neuropharmacology Oct 2021As for electronic computation, neural information processing is energetically expensive. This is because information is coded in the brain as membrane voltage changes,... (Review)
Review
As for electronic computation, neural information processing is energetically expensive. This is because information is coded in the brain as membrane voltage changes, which are generated largely by passive ion movements down electrochemical gradients, and these ion movements later need to be reversed by active ATP-dependent ion pumping. This article will review how much of the energetic cost of the brain reflects the activity of glutamatergic synapses, consider the relative amount of energy used pre- and postsynaptically, outline how evolution has energetically optimised synapse function by adjusting the presynaptic release probability and the postsynaptic number of glutamate receptors, and speculate on how energy use by synapses may be sensed and adjusted. This article is part of the special Issue on 'Glutamate Receptors - The Glutamatergic Synapse'.
Topics: Adenosine Triphosphate; Animals; Electrophysiological Phenomena; Energy Metabolism; Glutamic Acid; Humans; Synapses
PubMed: 34314736
DOI: 10.1016/j.neuropharm.2021.108727 -
Neurobiology of Disease Feb 2023GABA is the major inhibitory neurotransmitter in the mature CNS. When GABA receptors are activated the membrane potential is driven towards hyperpolarization due to... (Review)
Review
GABA is the major inhibitory neurotransmitter in the mature CNS. When GABA receptors are activated the membrane potential is driven towards hyperpolarization due to chloride entry into the neuron. However, chloride ion dysregulation that alters the ionic gradient can result in depolarizing GABAergic post-synaptic potentials instead. In this review, we highlight that GABAergic inhibition prevents and restrains focal seizures but then reexamine this notion in the context of evidence that a static and/or a dynamic chloride ion dysregulation, that increases intracellular chloride ion concentrations, promotes epileptiform activity and seizures. To reconcile these findings, we hypothesize that epileptogenic pathologically interconnected neuron (PIN) microcircuits, representing a small minority of neurons, exhibit static chloride dysregulation and should exhibit depolarizing inhibitory post-synaptic potentials (IPSPs). We speculate that chloride ion dysregulation and PIN cluster activation may generate fast ripples and epileptiform spikes as well as initiate the hypersynchronous seizure onset pattern and microseizures. Also, we discuss the genetic, molecular, and cellular players important in chloride dysregulation which regulate epileptogenesis and initiate the low-voltage fast seizure onset pattern. We conclude that chloride dysregulation in neuronal networks appears to be critical for epileptogenesis and seizure genesis, but feed-back and feed-forward inhibitory GABAergic neurotransmission plays an important role in preventing and restraining seizures as well.
Topics: Humans; Chlorides; Neurons; Seizures; Synaptic Transmission; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 36638891
DOI: 10.1016/j.nbd.2023.106000 -
Journal of Molecular Biology Jan 2023Signal transduction at the synapse is mediated by a variety of protein-lipid interactions, which are vital for the spatial and temporal regulation of synaptic vesicle... (Review)
Review
Signal transduction at the synapse is mediated by a variety of protein-lipid interactions, which are vital for the spatial and temporal regulation of synaptic vesicle biogenesis, neurotransmitter release, and postsynaptic receptor activation. Therefore, our understanding of synaptic transmission cannot be completed until the elucidation of these critical protein-lipid interactions. On this front, recent advances in nanodiscs have vastly expanded our ability to probe and reprogram membrane biology in synapses. Here, we summarize the progress of the nanodisc toolbox and discuss future directions in this exciting field.
Topics: Synapses; Synaptic Transmission; Synaptic Vesicles; Lipid Metabolism; Nanostructures; Membrane Proteins
PubMed: 35872069
DOI: 10.1016/j.jmb.2022.167757 -
Molecular and Cellular Neurosciences Jun 2020Neuronal dendrites are highly branched and specialized compartments with distinct structures and secretory organelles (e.g., spines, Golgi outposts), and a unique... (Review)
Review
Neuronal dendrites are highly branched and specialized compartments with distinct structures and secretory organelles (e.g., spines, Golgi outposts), and a unique cytoskeletal organization that includes microtubules of mixed polarity. Dendritic membranes are enriched with proteins, which specialize in the formation and function of the post-synaptic membrane of the neuronal synapse. How these proteins partition preferentially in dendrites, and how they traffic in a manner that is spatiotemporally accurate and regulated by synaptic activity are long-standing questions of neuronal cell biology. Recent studies have shed new insights into the spatial control of dendritic membrane traffic, revealing new classes of proteins (e.g., septins) and cytoskeleton-based mechanisms with dendrite-specific functions. Here, we review these advances by revisiting the fundamental mechanisms that control membrane traffic at the levels of protein sorting and motor-driven transport on microtubules and actin filaments. Overall, dendrites possess unique mechanisms for the spatial control of membrane traffic, which might have specialized and co-evolved with their highly arborized morphology.
Topics: Animals; Cytoskeleton; Dendrites; Golgi Apparatus; Humans; Microtubules; Neurons; Protein Transport
PubMed: 32294508
DOI: 10.1016/j.mcn.2020.103492 -
Journal of Translational Medicine Oct 2023Seizures are associated with a decrease in γ-aminobutyric type A acid receptors (GABAaRs) on the neuronal surface, which may be regulated by enhanced internalization of...
BACKGROUND
Seizures are associated with a decrease in γ-aminobutyric type A acid receptors (GABAaRs) on the neuronal surface, which may be regulated by enhanced internalization of GABAaRs. When interactions between GABAaR subunit α-1 (GABRA1) and postsynaptic scaffold proteins are weakened, the α1-containing GABAaRs leave the postsynaptic membrane and are internalized. Previous evidence suggested that neuroplastin (NPTN) promotes the localization of GABRA1 on the postsynaptic membrane. However, the association between NPTN and GABRA1 in seizures and its effect on the internalization of α1-containing GABAaRs on the neuronal surface has not been studied before.
METHODS
An in vitro seizure model was constructed using magnesium-free extracellular fluid, and an in vivo model of status epilepticus (SE) was constructed using pentylenetetrazole (PTZ). Additionally, in vitro and in vivo NPTN-overexpression models were constructed. Electrophysiological recordings and internalization assays were performed to evaluate the action potentials and miniature inhibitory postsynaptic currents of neurons, as well as the intracellular accumulation ratio of α1-containing GABAaRs in neurons. Western blot analysis was performed to detect the expression of GABRA1 and NPTN both in vitro and in vivo. Immunofluorescence co-localization analysis and co-immunoprecipitation were performed to evaluate the interaction between GABRA1 and NPTN.
RESULTS
The expression of GABRA1 was found to be decreased on the neuronal surface both in vivo and in vitro seizure models. In the in vitro seizure model, α1-containing GABAaRs showed increased internalization. NPTN expression was found to be positively correlated with GABRA1 expression on the neuronal surface both in vivo and in vitro seizure models. In addition, NPTN overexpression alleviated seizures and NPTN was shown to bind to GABRA1 to form protein complexes that can be disrupted during seizures in both in vivo and in vitro models. Furthermore, NPTN was found to inhibit the internalization of α1-containing GABAaRs in the in vitro seizure model.
CONCLUSION
Our findings provide evidence that NPTN may exert antiepileptic effects by binding to GABRA1 to inhibit the internalization of α1-containing GABAaRs.
Topics: Humans; Anticonvulsants; Carrier Proteins; gamma-Aminobutyric Acid; Neurons; Receptors, GABA-A; Seizures
PubMed: 37814294
DOI: 10.1186/s12967-023-04596-4 -
Cells Oct 2022The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic...
The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic synapses, it is established that the presence of astrocytic processes and their structural arrangements varies considerably between and within brain regions and between synapses of the same neuron. In contrast, less is known about the organization of astrocytic processes at GABAergic synapses although bi-directional signaling is known to exist at these synapses too. Therefore, we established super-resolution expansion microscopy of GABAergic synapses and nearby astrocytic processes in the of the mouse hippocampal CA1 region. By visualizing the presynaptic vesicular GABA transporter and the postsynaptic clustering protein gephyrin, we documented the subsynaptic heterogeneity of GABAergic synaptic contacts. We then compared the volume distribution of astrocytic processes near GABAergic synapses between individual synapses and with glutamatergic synapses. We made two novel observations. First, astrocytic processes were more abundant at the GABAergic synapses with large postsynaptic gephyrin clusters. Second, astrocytic processes were less abundant in the vicinity of GABAergic synapses compared to glutamatergic, suggesting that the latter may be selectively approached by astrocytes. Because of the GABA transporter distribution, we also speculate that this specific arrangement enables more efficient re-uptake of GABA into presynaptic terminals.
Topics: Animals; GABA Plasma Membrane Transport Proteins; Mice; Presynaptic Terminals; Receptors, GABA-A; Synapses; gamma-Aminobutyric Acid
PubMed: 36231112
DOI: 10.3390/cells11193150