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Wiley Interdisciplinary Reviews.... Sep 2019Small arteries in the body control vascular resistance, and therefore, blood pressure and blood flow. Endothelial and smooth muscle cells in the arterial walls respond... (Review)
Review
Small arteries in the body control vascular resistance, and therefore, blood pressure and blood flow. Endothelial and smooth muscle cells in the arterial walls respond to various stimuli by altering the vascular resistance on a moment to moment basis. Smooth muscle cells can directly influence arterial diameter by contracting or relaxing, whereas endothelial cells that line the inner walls of the arteries modulate the contractile state of surrounding smooth muscle cells. Cytosolic calcium is a key driver of endothelial and smooth muscle cell functions. Cytosolic calcium can be increased either by calcium release from intracellular stores through IP3 or ryanodine receptors, or the influx of extracellular calcium through ion channels at the cell membrane. Depending on the cell type, spatial localization, source of a calcium signal, and the calcium-sensitive target activated, a particular calcium signal can dilate or constrict the arteries. Calcium signals in the vasculature can be classified into several types based on their source, kinetics, and spatial and temporal properties. The calcium signaling mechanisms in smooth muscle and endothelial cells have been extensively studied in the native or freshly isolated cells, therefore, this review is limited to the discussions of studies in native or freshly isolated cells. This article is categorized under: Biological Mechanisms > Cell Signaling Laboratory Methods and Technologies > Imaging Models of Systems Properties and Processes > Mechanistic Models.
Topics: Animals; Calcium; Calcium Channels, L-Type; Calcium Signaling; Endothelium, Vascular; Humans; Inositol 1,4,5-Trisphosphate Receptors; Ryanodine Receptor Calcium Release Channel; Transient Receptor Potential Channels
PubMed: 30884210
DOI: 10.1002/wsbm.1448 -
Antioxidants & Redox Signaling Oct 2019Pulmonary hypertension (PH) is characterized by elevated vascular resistance due to vasoconstriction and remodeling of the normally low-pressure pulmonary vasculature.... (Review)
Review
Pulmonary hypertension (PH) is characterized by elevated vascular resistance due to vasoconstriction and remodeling of the normally low-pressure pulmonary vasculature. Redox stress contributes to the pathophysiology of this disease by altering the regulation and activity of membrane receptors, K channels, and intracellular Ca homeostasis. Antioxidant therapies have had limited success in treating PH, leading to a growing appreciation that reductive stress, in addition to oxidative stress, plays a role in metabolic and cell signaling dysfunction in pulmonary vascular cells. Reactive oxygen species generation from mitochondria and NADPH oxidases has substantial effects on K conductance and membrane potential, and both receptor-operated and store-operated Ca entry. Some specific redox changes resulting from oxidation, S-nitrosylation, and S-glutathionylation are known to modulate membrane receptor and ion channel activity in PH. However, many sites of regulation that have been elucidated in nonpulmonary cell types have not been tested in the pulmonary vasculature, and context-specific molecular mechanisms are lacking. Here, we review what is known about redox regulation of membrane receptors and ion channels in PH. Further investigation of the mechanisms involved is needed to better understand the etiology of PH and develop better targeted treatment strategies.
Topics: Animals; Calcium; Humans; Hypertension, Pulmonary; Ion Channels; Oxidation-Reduction; Potassium; Receptors, Cytoplasmic and Nuclear; Vascular Resistance
PubMed: 30569735
DOI: 10.1089/ars.2018.7699 -
Nature Communications May 2022NALCN channel mediates sodium leak currents and is important for maintaining proper resting membrane potential. NALCN and FAM155A form the core complex of the channel,...
NALCN channel mediates sodium leak currents and is important for maintaining proper resting membrane potential. NALCN and FAM155A form the core complex of the channel, the activity of which essentially depends on the presence of both UNC79 and UNC80, two auxiliary proteins. NALCN, FAM155A, UNC79, and UNC80 co-assemble into a large hetero-tetrameric channel complex. Genetic mutations of NALCN channel components lead to neurodevelopmental diseases. However, the structure and mechanism of the intact channel complex remain elusive. Here, we present the cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex. The structure shows that UNC79-UNC80 form a large piler-shaped heterodimer which was tethered to the intracellular side of the NALCN channel through tripartite interactions with the cytoplasmic loops of NALCN. Two interactions are essential for proper cell surface localization of NALCN. The other interaction relieves the self-inhibition of NALCN by pulling the auto-inhibitory CTD Interacting Helix (CIH) out of its binding site. Our work defines the structural mechanism of NALCN modulation by UNC79 and UNC80.
Topics: Animals; Ion Channels; Mammals; Membrane Potentials; Membrane Proteins; Mutation; Protein Domains
PubMed: 35550517
DOI: 10.1038/s41467-022-30403-7 -
The Journal of Physiology Jan 2023Autosomal dominant polycystic kidney disease is caused by mutations in the membrane receptor PKD1 or the cation channel PKD2. TACAN (also termed TMEM120A), recently...
Autosomal dominant polycystic kidney disease is caused by mutations in the membrane receptor PKD1 or the cation channel PKD2. TACAN (also termed TMEM120A), recently reported as an ion channel in neurons for mechanosensing and pain sensing, is also distributed in diverse non-neuronal tissues, such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in a complex with PKD2 in native renal cell lines. Using the two-electrode voltage clamp in Xenopus oocytes, we found that TACAN inhibits the channel activity of PKD2 gain-of-function mutant F604P. TACAN fragments containing the first and last transmembrane domains interacted with the PKD2 C- and N-terminal fragments, respectively. The TACAN N-terminus acted as a blocking peptide, and TACAN inhibited the function of PKD2 by the binding of PKD2 with TACAN. By patch clamping in mammalian cells, we found that TACAN inhibits both the single-channel conductance and the open probability of PKD2 and mutant F604P. PKD2 co-expressed with TACAN, but not PKD2 alone, exhibited pressure sensitivity. Furthermore, we found that TACAN aggravates PKD2-dependent tail curvature and pronephric cysts in larval zebrafish. In summary, this study revealed that TACAN acts as a PKD2 inhibitor and mediates mechanosensitivity of the PKD2-TACAN channel complex. KEY POINTS: TACAN inhibits the function of PKD2 in vitro and in vivo. TACAN N-terminal S1-containing fragment T160X interacts with the PKD2 C-terminal fragment N580-L700, and its C-terminal S6-containing fragment L296-D343 interacts with the PKD2 N-terminal A594X. TACAN inhibits the function of the PKD2 channel by physical interaction. The complex of PKD2 with TACAN, but not PKD2 alone, confers mechanosensitivity.
Topics: Animals; Zebrafish; TRPP Cation Channels; Ion Channels; Polycystic Kidney, Autosomal Dominant; Kidney; Mammals
PubMed: 36420836
DOI: 10.1113/JP283895 -
Trends in Neurosciences Feb 2020During prenatal brain development, ion channels are ubiquitous across several cell types, including progenitor cells and migrating neurons but their function has not... (Review)
Review
During prenatal brain development, ion channels are ubiquitous across several cell types, including progenitor cells and migrating neurons but their function has not been clear. In the past, ion channel dysfunction has been primarily studied in the context of postnatal, differentiated neurons that fire action potentials - notably ion channels mutated in the epilepsies - yet data now support a surprising role in prenatal human brain disorders as well. Modern gene discovery approaches have identified defective ion channels in individuals with cerebral cortex malformations, which reflect abnormalities in early-to-middle stages of embryonic development (prior to ubiquitous action potentials). These human genetics studies and recent in utero animal modeling work suggest that precise control of ionic flux (calcium, sodium, and potassium) contributes to in utero developmental processes such as neural proliferation, migration, and differentiation.
Topics: Action Potentials; Animals; Brain; Epilepsy; Female; Humans; Ion Channels; Neurons; Pregnancy
PubMed: 31959360
DOI: 10.1016/j.tins.2019.12.004 -
British Journal of Pharmacology Nov 2019The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels... (Review)
Review
The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria-specific channels. However, many ion channels have multiple localizations within the cell, hampering a clear-cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels, with special focus on the channels that have received much attention in recent years, namely, the voltage-dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane-located potassium channels. In addition, possible strategies to overcome the difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interacting partners. Altogether, these promising tools along with large-scale chemical screenings set up to identify new, specific channel modulators will hopefully allow us to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischaemic damage and cancer. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.
Topics: Animals; Humans; Ion Channels; Membrane Transport Modulators; Mitochondria
PubMed: 30440086
DOI: 10.1111/bph.14544 -
Current Opinion in Neurobiology Aug 2019Ion channels are microscopic pore proteins in the membrane that open and close in response to chemical and electrical stimuli. This simple concept underlies rapid... (Review)
Review
Ion channels are microscopic pore proteins in the membrane that open and close in response to chemical and electrical stimuli. This simple concept underlies rapid electrical signaling in the brain as well as several important aspects of neural plasticity. Although the soma accounts for less than 1% of many neurons by membrane area, it has been the major site of measuring ion channel function. However, the axon is one of the longest processes found in cellular biology and hosts a multitude of critical signaling functions in the brain. Not only does the axon initiate and rapidly propagate action potentials (APs) across the brain but it also forms the presynaptic terminals that convert these electrical inputs into chemical outputs. Here, we review recent advances in the physiological role of ion channels within the diverse landscape of the axon and presynaptic terminals.
Topics: Action Potentials; Axons; Ion Channels; Neurons; Presynaptic Terminals
PubMed: 30784979
DOI: 10.1016/j.conb.2019.01.020 -
Nature Communications Jul 2022N-methyl-D-aspartate receptors (NMDARs) are transmembrane proteins that are activated by the neurotransmitter glutamate and are found at most excitatory vertebrate...
N-methyl-D-aspartate receptors (NMDARs) are transmembrane proteins that are activated by the neurotransmitter glutamate and are found at most excitatory vertebrate synapses. NMDAR channel blockers, an antagonist class of broad pharmacological and clinical significance, inhibit by occluding the NMDAR ion channel. A vast literature demonstrates that NMDAR channel blockers, including MK-801, phencyclidine, ketamine, and the Alzheimer's disease drug memantine, can bind and unbind only when the NMDAR channel is open. Here we use electrophysiological recordings from transfected tsA201 cells and cultured neurons, NMDAR structural modeling, and custom-synthesized compounds to show that NMDAR channel blockers can enter the channel through two routes: the well-known hydrophilic path from extracellular solution to channel through the open channel gate, and also a hydrophobic path from plasma membrane to channel through a gated fenestration ("membrane-to-channel inhibition" (MCI)). Our demonstration that ligand-gated channels are subject to MCI, as are voltage-gated channels, highlights the broad expression of this inhibitory mechanism.
Topics: Dizocilpine Maleate; Ion Channels; Ketamine; Memantine; Receptors, N-Methyl-D-Aspartate
PubMed: 35840593
DOI: 10.1038/s41467-022-31817-z -
Cell Communication and Signaling : CCS Mar 2022Store-operated channels (SOCs) are highly selective Ca2+ channels that mediate Ca2+ influx in non-excitable and excitable (i.e., skeletal and cardiac muscle) cells.... (Review)
Review
Store-operated channels (SOCs) are highly selective Ca2+ channels that mediate Ca2+ influx in non-excitable and excitable (i.e., skeletal and cardiac muscle) cells. These channels are triggered by Ca2+ depletion of the endoplasmic reticulum and sarcoplasmic reticulum, independently of inositol 1,4,5-trisphosphate (InsP3), which is involved in cell growth, differentiation, and gene transcription. When the Ca2+ store is depleted, stromal interaction molecule1 (STIM1) as Ca2+ sensor redistributes into discrete puncta near the plasma membrane and activates the protein Ca2+ release activated Ca2+ channel protein 1 (Orai1). Accumulating evidence suggests that SOC is associated with several physiological roles in endothelial dysfunction and vascular smooth muscle proliferation that contribute to the progression of cardiovascular disease. This review mainly elaborates on the contribution of SOC in the vasculature (endothelial cells and vascular smooth muscle cells). We will further retrospect the literature implicating a critical role for these proteins in cardiovascular disease. Video Abstract.
Topics: Calcium; Calcium Channels; Calcium Signaling; Cardiovascular Diseases; Endothelial Cells; Humans; ORAI1 Protein; Stromal Interaction Molecule 1
PubMed: 35303866
DOI: 10.1186/s12964-022-00829-z -
Life Science Alliance Feb 2023Muscle satellite cells (MuSCs), myogenic stem cells in skeletal muscles, play an essential role in muscle regeneration. After skeletal muscle injury, quiescent MuSCs are...
Muscle satellite cells (MuSCs), myogenic stem cells in skeletal muscles, play an essential role in muscle regeneration. After skeletal muscle injury, quiescent MuSCs are activated to enter the cell cycle and proliferate, thereby initiating regeneration; however, the mechanisms that ensure successful MuSC division, including chromosome segregation, remain unclear. Here, we show that PIEZO1, a calcium ion (Ca)-permeable cation channel activated by membrane tension, mediates spontaneous Ca influx to control the regenerative function of MuSCs. Our genetic engineering approach in mice revealed that PIEZO1 is functionally expressed in MuSCs and that deletion in these cells delays myofibre regeneration after injury. These results are, at least in part, due to a mitotic defect in MuSCs. Mechanistically, this phenotype is caused by impaired PIEZO1-Rho signalling during myogenesis. Thus, we provide the first concrete evidence that PIEZO1, a bona fide mechanosensitive ion channel, promotes proliferation and regenerative functions of MuSCs through precise control of cell division.
Topics: Animals; Mice; Chromosome Segregation; Ion Channels; Muscle, Skeletal; Myoblasts; Signal Transduction; Satellite Cells, Skeletal Muscle; Regeneration
PubMed: 36446523
DOI: 10.26508/lsa.202201783