Neuronal Glutamatergic Synaptic Clefts Alkalinize Rather Than Acidify during Neurotransmission DOI Creative Commons
Michał Stawarski, Roberto X. Hernandez, Touhid Feghhi

et al.

Journal of Neuroscience, Journal Year: 2020, Volume and Issue: 40(8), P. 1611 - 1624

Published: Jan. 21, 2020

The dogma that the synaptic cleft acidifies during neurotransmission is based on corelease of neurotransmitters and protons from vesicles, supported by direct data sensory ribbon-type synapses. However, it unclear whether acidification occurs at non–ribbon-type Here we used genetically encoded fluorescent pH indicators to examine conventional neuronal At neuromuscular junction female Drosophila larvae, observed alkaline spikes over 1 log unit fictive locomotion in vivo. Ex vivo , single action potentials evoked alkalinizing transients only ∼0.01 unit, but these summated rapidly burst firing. A chemical indicator targeted corroborated findings. Cleft were dependent Ca 2+ movement across postsynaptic membrane, rather than neurotransmitter release per se, a result consistent with alkalinization being driven /H + antiporting activity plasma membrane -ATPase membrane. Targeting microenvironment presynaptic voltage gated channels revealed also occurred within proper active zone not just extrasynaptic regions. Application mouse calyx Held, mammalian central synapse, similarly firing both males females. These findings, made two quite different non–ribbon type synapses, suggest neurotransmission, acidification, generalizable phenomenon SIGNIFICANCE STATEMENT Neurotransmission highly sensitive extracellular milieu. This readily evident neurological symptoms accompany systemic acid/base imbalances. Imaging synapses show itself can acidify cleft, likely due glutamate. It clear same difficulties collecting such data. If does occur, would provide for an additional layer activity-dependent modulation neurotransmission. Our findings alkalinization, encourages reassessment scope influences short-term plasticity.

Language: Английский

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels DOI Open Access
Kasper B. Hansen, Lonnie P. Wollmuth, Derek Bowie

et al.

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(4), P. 1469 - 1658

Published: Oct. 1, 2021

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels critical to brain function and centrally implicated numerous psychiatric neurologic disorders. There different classes iGluRs with a variety receptor subtypes each class that play distinct roles neuronal functions. The diversity iGluR subtypes, their unique functional properties roles, has motivated large number studies. Our understanding advanced considerably since first subunit gene was cloned 1989, research focus expanded encompass facets biology have been recently discovered exploit experimental paradigms made possible technological advances. Here, we review insights from more than 3 decades studies an emphasis on progress occurred past decade. We cover structure, function, pharmacology, neurophysiology, therapeutic implications for all assembled subunits encoded 18 genes. SIGNIFICANCE STATEMENT: Glutamate important virtually aspects either involved mediating some clinical features neurological disease or represent target treatment. Therefore, pharmacology this will advance our many at molecular, cellular, system levels provide new opportunities treat patients.

Language: Английский

Citations

466
Interactions by Disorder – A Matter of Context DOI Creative Commons
Katrine Bugge, Inna Brakti, Catarina B. Fernandes

et al.

Frontiers in Molecular Biosciences, Journal Year: 2020, Volume and Issue: 7

Published: June 16, 2020

Living organisms depend on timely and organized interactions between proteins linked in interactomes of high complexity. The recent increased precision by which protein can be studied, the enclosure intrinsic structural disorder, suggest that it is time to zoom out embrace beyond most central points physical encounter. present paper discusses protein-protein view disorder with an emphasis flanking regions contexts disorder-based interactions. Context constitutes overarching concept being physicochemical, biomolecular, physiological nature, but also includes immediate molecular context interaction. For intrinsically disordered proteins, often function exploiting short linear motifs, contributes highly regulatory decisive manners constitute a yet largely unrecognized source interaction potential multitude biological processes. Through selected examples, this review emphasizes how multivalency, charges charge clusters, hydrophobic patches, dynamics, energetic frustration, ensemble redistribution or are emerging as important contributors allosteric regulation, positive negative cooperativity, feedback regulation selection binding. understanding context, particular role take interactions, untapped well modulation potential, relevance drug discovery development.

Language: Английский

Citations

158
The SLC9A-C Mammalian Na+/H+Exchanger Family: Molecules, Mechanisms, and Physiology DOI
Stine F. Pedersen, Laurent Counillon

Physiological Reviews, Journal Year: 2019, Volume and Issue: 99(4), P. 2015 - 2113

Published: Sept. 11, 2019

Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating electroneutral exchange Na+ H+ across cellular membranes. They belong to an ancient family highly evolutionarily conserved proteins, they essential physiological all phyla. In this review, we focus on mammalian (NHEs), solute carrier (SLC) 9 family. This transporters constitutes three branches: SLC9A, -B, -C. Within these, each isoform exhibits distinct expression profiles, regulation, roles. Some these are studied, with hundreds original articles, some still only rudimentarily understood. present discuss pioneering work as well current state-of-the-art research NHEs. We aim provide reader a comprehensive view core knowledge recent insights into member, from gene organization over protein structure regulation pathophysiological Particular attention is given integrated physiology NHEs main organ systems. several novel analyses useful overviews, pinpoint remaining enigmas, which hope will inspire versatile proteins.

Language: Английский

Citations

151
Ionic signalling in astroglia beyond calcium DOI Open Access
Alexei Verkhratsky, Verena Untiet, Christine R. Rose

et al.

The Journal of Physiology, Journal Year: 2019, Volume and Issue: 598(9), P. 1655 - 1670

Published: Feb. 8, 2019

Astrocytes are homeostatic and protective cells of the central nervous system. Astroglial responses tightly coordinated with neuronal activity. maintain excitability through regulation extracellular ion concentrations, as well assisting modulating synaptic transmission by uptake catabolism major neurotransmitters. Moreover, they support metabolism detoxify ammonium reactive oxygen species. actions initiated controlled intercellular signalling ions, including Ca2+ , Na+ Cl- H+ possibly K+ . This review summarises current knowledge on ionic signals mediated monovalent which occur in microdomains, global events, or propagating waves thereby represent substrate for astroglial excitability.

Language: Английский

Citations

85
The therapeutic importance of acid-base balance DOI Open Access
Bianca N. Quade, Mark D. Parker, Rossana Occhipinti

et al.

Biochemical Pharmacology, Journal Year: 2020, Volume and Issue: 183, P. 114278 - 114278

Published: Oct. 9, 2020

Language: Английский

Citations

72
The effect of Ferroptosis -related Mitochondrial Dysfunction in the Development of Temporal Lobe Epilepsy DOI

Yang Su,

Ningrui Cao,

Dingkun Zhang

et al.

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102248 - 102248

Published: Feb. 24, 2024

Language: Английский

Citations

9
pH regulating mechanisms of astrocytes: A critical component in physiology and disease of the brain DOI Creative Commons
Shefeeq M. Theparambil, Gulnaz Begum, Christine R. Rose

et al.

Cell Calcium, Journal Year: 2024, Volume and Issue: 120, P. 102882 - 102882

Published: April 8, 2024

Strict homeostatic control of pH in both intra- and extracellular compartments the brain is fundamentally important, primarily due to profound impact free protons ([H

Language: Английский

Citations

9
Protons as Messengers of Intercellular Communication in the Nervous System DOI Creative Commons

Enrique Soto,

Audrey Ortega-Ramírez, Rosario Vega

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: Oct. 10, 2018

Several studies demonstrated that the low pH of synaptic vesicles implies neurotransmitter release is always accompanied by co-release H+ into cleft, leading to transient extracellular shifts. Also, evidence has accumulated indicating various processes, including activation membrane transporters, increased production CO2 and metabolites, such as lactate, may produce significant shifts in nano- micro-domains central nervous system (CNS), constituting a reliable signal for intercellular communication. The mechanisms modulating proton concentration domains complex source protons network ion exchangers buffer capacity media finally establish or microdomains. Given strictly regulated variable multicellular organisms, localized changes constitute signals cellular processes occur cell group cells. ASICs function specific (not unique) sensors this signaling mechanism, detecting subtle variations range varying from 5 8. role extrasynaptic communication constitutes an old evolutionary have evolved metabolic state detection mechanism highly dependent mechanism. In study showing regulation its excitability systems reviewed, data regarding neurotransmission. Finally, we here propose relevant whose regulatory lead differential responses

Language: Английский

Citations

62
Activated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase DOI Creative Commons
Junli Zhao,

Jinyi Sun,

Yang Zheng

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 21, 2022

Epileptic seizures are widely regarded to occur as a result of the excitation-inhibition imbalance from neuro-centric view. Although astrocyte-neuron interactions increasingly recognized in seizure, elementary questions about causal role astrocytes seizure remain unanswered. Here we show that optogenetic activation channelrhodopsin-2-expressing effectively attenuates neocortical rodent models. This anti-seizure effect is independent classical calcium signaling, and instead related astrocytic Na+-K+-ATPase-mediated buffering K+, which activity-dependently inhibits firing highly active pyramidal neurons during seizure. Compared with inhibition neurons, astrocyte stimulation exhibits effects several advantages, including wider therapeutic window, large-space efficacy, minimal side effects. Finally, optogenetic-driven Na+-K+-ATPase shows promising chronic focal cortical dysplasia epilepsy model. Together, uncover strategy control activity, providing alternative ideas potential target for treatment intractable epilepsy.

Language: Английский

Citations

38
Potential for New Therapeutic Approaches by Targeting Lactate and pH Mediated Epigenetic Dysregulation in Major Mental Diseases DOI Creative Commons
Shabnam Nohesara, Hamid M. Abdolmaleky, Sam Thiagalingam

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(2), P. 457 - 457

Published: Feb. 18, 2024

Multiple lines of evidence have shown that lactate-mediated pH alterations in the brains patients with neuropsychiatric diseases such as schizophrenia (SCZ), Alzheimer’s disease (AD) and autism may be attributed to mitochondrial dysfunction changes energy metabolism. While neuronal activity is associated reduction brain pH, astrocytes are responsible for rebalancing maintain equilibrium. As lactate level main determinant activities impacted by due binding protons (H+) various types proteins, altering their structure function non-neuronal cells brain. Lactate could affect diverse epigenetic modifications, including histone lactylation, which linked acetylation DNA methylation. In this review, we discuss importance homeostasis normal function, role an essential regulatory molecule its contributions abnormalities diseases, shed light on lactate-based pH-modulating therapies targeting modifications. conclusion, attempt highlight potentials challenges translating lactate-pH-modulating clinics treatment diseases.

Language: Английский

Citations

8