scholarly journals Roles of Microglial Ion Channel in Neurodegenerative Diseases

2021 ◽  
Vol 10 (6) ◽  
pp. 1239
Author(s):  
Alexandru Cojocaru ◽  
Emilia Burada ◽  
Adrian-Tudor Bălșeanu ◽  
Alexandru-Florian Deftu ◽  
Bogdan Cătălin ◽  
...  
Keyword(s):  
Ion Channels ◽  
Neurodegenerative Diseases ◽  
Excitable Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
The Common ◽  
Transient Receptor ◽  
The Impact

As the average age and life expectancy increases, the incidence of both acute and chronic central nervous system (CNS) pathologies will increase. Understanding mechanisms underlying neuroinflammation as the common feature of any neurodegenerative pathology, we can exploit the pharmacology of cell specific ion channels to improve the outcome of many CNS diseases. As the main cellular player of neuroinflammation, microglia play a central role in this process. Although microglia are considered non-excitable cells, they express a variety of ion channels under both physiological and pathological conditions that seem to be involved in a plethora of cellular processes. Here, we discuss the impact of modulating microglia voltage-gated, potential transient receptor, chloride and proton channels on microglial proliferation, migration, and phagocytosis in neurodegenerative diseases.

scholarly journals Regulation of voltage-gated ion channels in excitable cells by the ubiquitin ligases Nedd4 and Nedd4-2

Channels ◽  
2011 ◽  
Vol 5 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Daria Bongiorno ◽  
Friderike Schuetz ◽  
Philip Poronnik ◽  
David J. Adams
Keyword(s):  
Ion Channels ◽  
Ubiquitin Ligases ◽  
Excitable Cells ◽  
Voltage Gated ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

scholarly journals TMEM266 is a functional voltage sensor regulated by extracellular Zn2+

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Ferenc Papp ◽  
Suvendu Lomash ◽  
Orsolya Szilagyi ◽  
Erika Babikow ◽  
Jaime Smith ◽  
...  
Keyword(s):  
Ion Channels ◽  
Unknown Function ◽  
Conformational Transition ◽  
Voltage Sensor ◽  
Structural Rearrangements ◽  
Future Studies ◽  
Proton Channels ◽  
Cellular Processes ◽  
Electrical Signaling ◽  
And Control

Voltage-activated ion channels contain S1-S4 domains that sense membrane voltage and control opening of ion-selective pores, a mechanism that is crucial for electrical signaling. Related S1-S4 domains have been identified in voltage-sensitive phosphatases and voltage-activated proton channels, both of which lack associated pore domains. hTMEM266 is a protein of unknown function that is predicted to contain an S1-S4 domain, along with partially structured cytoplasmic termini. Here we show that hTMEM266 forms oligomers, undergoes both rapid (µs) and slow (ms) structural rearrangements in response to changes in voltage, and contains a Zn2+ binding site that can regulate the slow conformational transition. Our results demonstrate that the S1-S4 domain in hTMEM266 is a functional voltage sensor, motivating future studies to identify cellular processes that may be regulated by the protein. The ability of hTMEM266 to respond to voltage on the µs timescale may be advantageous for designing new genetically encoded voltage indicators.

scholarly journals Broken symmetry in the human BK channel

2018 ◽  
Author(s):  
Lige Tonggu ◽  
Liguo Wang
Keyword(s):  
Ion Channels ◽  
Binding Sites ◽  
Bk Channel ◽  
Excitable Cells ◽  
Local Conformation ◽  
Channel Opening ◽  
Significant Movement ◽  
Em Method ◽  
The Common ◽  
Functional States

ABSTRACTVoltage-gated and ligand-modulated ion channels play critical roles in excitable cells. To understand the interplay among voltage-sensing, ligand-binding and channel opening, the structures of ion channels in various functional states need to be determined. Here, the “random spherically constrained” (RSC) single-particle cryo-EM method was employed to study the human large conductance voltage- and calcium-activated potassium (hBK or hSlo1) channels reconstituted into liposomes. The hBK structure has been determined at 3.5 Å resolution in the absence of Ca2+. Instead of the common four-fold symmetry observed in ligand-modulated ion channels, a two-fold symmetry was observed in hBK. Two opposing subunits in the Ca2+ sensing gating ring rotate around the center of each subunit, which results in the movement of the assembly and flexible interfaces and Ca2+ binding sites. Despite the significant movement, the local conformation of the assembly interfaces and Ca2+ binding sites remains the same among the four subunits.

Abstract 1073: Cardiac Voltage-gated Nav channel Na v 1.5 Requires An AnkyrinG-dependent Pathway For Targeting in Cardiomyocytes

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
John S Lowe ◽  
Oleg Palygin ◽  
Patrick Wright ◽  
Erwin Shibata ◽  
Peter Mohler
Keyword(s):  
Ion Channels ◽  
Site Directed Mutagenesis ◽  
Loss Of Function ◽  
Excitable Cells ◽  
Membrane Expression ◽  
Voltage Gated ◽  
Ankyrin G ◽  
Ankyrin B ◽  
Dependent Pathway

Membrane localization of ion channels is very important for normal function in excitable cells. In heart, voltage-gated Na + channels are necessary for the rapid upstroke of the cardiomyocyte action potential, and variants in SCN5A (encodes Na v 1.5) are associated with fatal arrhythmias. We have identified ankyrin family proteins as critical components for normal ion channel and transporter targeting in cardiomyocytes. Humans with ANK2 (encodes ankyrin-B) loss of function variants display abnormal cardiac phenotypes and risk for sudden cardiac death. Mice that lack ankyrin-B expression display a similar phenotype. Our most recent results demonstrate that a second ankyrin gene product, ankyrin-G (encoded by ANK 3) is critical for targeting Na v 1.5 to specific cardiomyocyte membrane domains. We assessed the hypothesis that Na v 1.5 membrane expression and localization is controlled by an ankyrin-G-dependent pathway and disruption of ankyrin-G/Na v 1.5 interactions lead to human cardiac disease in this study. We used a combination of techniques including biochemistry, confocal microscopy, lentiviral expression, and electrophysiology to evaluate the functional relationship between ankyrin-G and Na v 1.5. We defined the structural elements on ankyrin-G and Na v 1.5 for their interaction using site-directed mutagenesis and in vitro binding assays. Lentiviral expression of shRNA targeted to rat 190 kD ankyrin-G effectively reduced the expression of ankyrin-G with a concomitant reduction of Na v 1.5 in immunofluorescence and immunoblot assays. Further-more, primary cardiomyocytes with reduced ankyrin-G expression have a significant reduction in Na + current density with no evident biophysical effects on Ca 2+ current or inactivation-gating of Na v 1.5 These results confirm the importance of ankyrin polypeptides for normal cardiac function and shed new light on the importance of intracellular trafficking pathways for the delivery and stability of critical ion channels and transporters in excitable cells.

To be or not to be cell autonomous? Autophagy says both

2017 ◽  
Vol 61 (6) ◽  
pp. 649-661 ◽  
Author(s):  
Nina Fenouille ◽  
Anna Chiara Nascimbeni ◽  
Joëlle Botti-Millet ◽  
Nicolas Dupont ◽  
Etienne Morel ◽  
...  
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Neurodegenerative Diseases ◽  
Building Blocks ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
Surrounding Environment ◽  
Selective Population ◽  
Different Types ◽  
Cytoplasmic Content

Although cells are a part of the whole organism, classical dogma emphasizes that individual cells function autonomously. Many physiological and pathological conditions, including cancer, and metabolic and neurodegenerative diseases, have been considered mechanistically as cell-autonomous pathologies, meaning those that damage or defect within a selective population of affected cells suffice to produce disease. It is becoming clear, however, that cells and cellular processes cannot be considered in isolation. Best known for shuttling cytoplasmic content to the lysosome for degradation and repurposing of recycled building blocks such as amino acids, nucleotides, and fatty acids, autophagy serves a housekeeping function in every cell and plays key roles in cell development, immunity, tissue remodeling, and homeostasis with the surrounding environment and the distant organs. In this review, we underscore the importance of taking interactions with the microenvironment into consideration while addressing the cell autonomous and non-autonomous functions of autophagy between cells of the same and different types and in physiological and pathophysiological situations.

scholarly journals Alteration of Sphingolipids in Biofluids: Implications for Neurodegenerative Diseases

2019 ◽  
Vol 20 (14) ◽  
pp. 3564 ◽  
Author(s):  
Luciana M. Pujol-Lereis
Keyword(s):  
Neurodegenerative Diseases ◽  
Therapeutic Option ◽  
Acyl Chain ◽  
Comprehensive Review ◽  
Cellular Processes ◽  
Acyl Chain Length ◽  
Sphingosine 1 Phosphate ◽  
Cellular Pathways ◽  
Specific Species ◽  
The Impact

Sphingolipids (SL) modulate several cellular processes including cell death, proliferation and autophagy. The conversion of sphingomyelin (SM) to ceramide and the balance between ceramide and sphingosine-1-phosphate (S1P), also known as the SL rheostat, have been associated with oxidative stress and neurodegeneration. Research in the last decade has focused on the possibility of targeting the SL metabolism as a therapeutic option; and SL levels in biofluids, including serum, plasma, and cerebrospinal fluid (CSF), have been measured in several neurodegenerative diseases with the aim of finding a diagnostic or prognostic marker. Previous reviews focused on results from diseases such as Alzheimer’s Disease (AD), evaluated total SL or species levels in human biofluids, post-mortem tissues and/or animal models. However, a comprehensive review of SL alterations comparing results from several neurodegenerative diseases is lacking. The present work compiles data from circulating sphingolipidomic studies and attempts to elucidate a possible connection between certain SL species and neurodegeneration processes. Furthermore, the effects of ceramide species according to their acyl-chain length in cellular pathways such as apoptosis and proliferation are discussed in order to understand the impact of the level alteration in specific species. Finally, enzymatic regulations and the possible influence of insulin resistance in the level alteration of SL are evaluated.

scholarly journals STIM Proteins and Glutamate Receptors in Neurons: Role in Neuronal Physiology and Neurodegenerative Diseases

2019 ◽  
Vol 20 (9) ◽  
pp. 2289 ◽  
Author(s):  
Karolina Serwach ◽  
Joanna Gruszczynska-Biegala
Keyword(s):  
Traumatic Brain Injury ◽  
Neurodegenerative Diseases ◽  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Neurodegenerative Disorders ◽  
Present Evidence ◽  
Voltage Gated ◽  
Pathological Conditions ◽  
Neuronal Physiology ◽  
Ca2 Channels

Neuronal calcium (Ca2+) influx has long been ascribed mainly to voltage-gated Ca2+ channels and glutamate receptor channels. Recent research has shown that it is also complemented by stromal interaction molecule (STIM) protein-mediated store-operated Ca2+ entry (SOCE). SOCE is described as Ca2+ flow into cells in response to the depletion of endoplasmic reticulum Ca2+ stores. The present review summarizes recent studies that indicate a relationship between neuronal SOCE that is mediated by STIM1 and STIM2 proteins and glutamate receptors under both physiological and pathological conditions, such as neurodegenerative disorders. We present evidence that the dysregulation of neuronal SOCE and glutamate receptor activity are hallmarks of acute neurodegenerative diseases (e.g., traumatic brain injury and cerebral ischemia) and chronic neurodegenerative diseases (e.g., Alzheimer’s disease and Huntington’s disease). Emerging evidence indicates a role for STIM proteins and glutamate receptors in neuronal physiology and pathology, making them potential therapeutic targets.

scholarly journals Opening TRPP2 (PKD2L1) requires the transfer of gating charges

2019 ◽  
Vol 116 (31) ◽  
pp. 15540-15549 ◽  
Author(s):  
Leo C. T. Ng ◽  
Thuy N. Vien ◽  
Vladimir Yarov-Yarovoy ◽  
Paul G. DeCaen
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Voltage Gated ◽  
State Dependent ◽  
Transient Receptor ◽  
Voltage Gated Ion Channels ◽  
Gating Charges ◽  
Gated Ion Channels

The opening of voltage-gated ion channels is initiated by transfer of gating charges that sense the electric field across the membrane. Although transient receptor potential ion channels (TRP) are members of this family, their opening is not intrinsically linked to membrane potential, and they are generally not considered voltage gated. Here we demonstrate that TRPP2, a member of the polycystin subfamily of TRP channels encoded by the PKD2L1 gene, is an exception to this rule. TRPP2 borrows a biophysical riff from canonical voltage-gated ion channels, using 2 gating charges found in its fourth transmembrane segment (S4) to control its conductive state. Rosetta structural prediction demonstrates that the S4 undergoes ∼3- to 5-Å transitional and lateral movements during depolarization, which are coupled to opening of the channel pore. Here both gating charges form state-dependent cation–π interactions within the voltage sensor domain (VSD) during membrane depolarization. Our data demonstrate that the transfer of a single gating charge per channel subunit is requisite for voltage, temperature, and osmotic swell polymodal gating of TRPP2. Taken together, we find that irrespective of stimuli, TRPP2 channel opening is dependent on activation of its VSDs.

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