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Current Topics in Membranes 2020Myogenic tone is a hall-mark feature of arterioles in the microcirculation. This pressure-induced, contractile activation of vascular smooth muscle cells (VSMCs) in the... (Review)
Review
Myogenic tone is a hall-mark feature of arterioles in the microcirculation. This pressure-induced, contractile activation of vascular smooth muscle cells (VSMCs) in the wall of these microvessels importantly contributes to the regulation and maintenance of blood pressure; blood flow to and within organs and tissues; and capillary pressure and fluid balance. Ion channels play a central role in the genesis and maintenance of myogenic tone. Mechanosensitive ion channels such as TRPC6 may serve as one of the sensors of pressure-induced membrane stress/strain, and TRPC6 along with TRPM4 channels are responsible pressure-induced VSMC depolarization that may be bolstered by the activity of Ca-activated Cl channels and inhibition of voltage-gated K (K) channels, inwardly-rectifying K (K) channels and ATP-sensitive K (K) channels. Membrane potential depolarization activates voltage-gated Ca channels (VGCCs), with CaV1.2 channels playing a central role. Calcium entry through CaV1.2 channels, which is amplified by Ca release through IP receptors in the form of Ca waves in some arterioles, provides the major source of activator calcium responsible for arteriolar myogenic tone. Stabilizing negative-feedback comes from depolarization- and Ca-induced activation of large-conductance Ca-activated K channels and depolarization-induced activation of K channels. Myogenic tone also is dampened by tonic activity of K and K channels. While much has been learned about ion channel expression and function in myogenic tone, additional studies are required to fill in our knowledge gaps due to significant regional differences in ion channel expression and function and a lack of data specifically from VSMCs in arterioles.
Topics: Animals; Arterioles; Calcium; Humans; Ion Channels; Muscle Development; Muscle, Smooth, Vascular
PubMed: 32402640
DOI: 10.1016/bs.ctm.2020.01.002 -
Progress in Biophysics and Molecular... 2022This retrospective traces the hypothesis of ion channels from an early statement in a 1970 essay in this journal (Hille, B., 1970, Prog. Biophys. Mol. Biol. 21, 1-32) to... (Review)
Review
This retrospective traces the hypothesis of ion channels from an early statement in a 1970 essay in this journal (Hille, B., 1970, Prog. Biophys. Mol. Biol. 21, 1-32) to its realization today in biophysical, molecular, biochemical, and structural terms. The Na and K channels of the action potential have been isolated, reconstituted, cloned, mutated, and expressed. They are conformationally flexible, multi-pass glycosylated membrane proteins. Refined atomic structures of several conformational states are known. The discoveries over this half century history illustrate the growth of a field from initial ideas to a mature discipline of biology, physiology, and biomedical science.
Topics: Ion Channels; Ions; Potassium; Retrospective Studies; Sodium
PubMed: 34856230
DOI: 10.1016/j.pbiomolbio.2021.11.003 -
Annals of Neurology Feb 2020It is generally thought that muscle excitability is almost exclusively controlled by currents responsible for generation of action potentials. We propose that smaller... (Review)
Review
It is generally thought that muscle excitability is almost exclusively controlled by currents responsible for generation of action potentials. We propose that smaller ion channel currents that contribute to setting the resting potential and to subthreshold fluctuations in membrane potential can also modulate excitability in important ways. These channels open at voltages more negative than the action potential threshold and are thus termed subthreshold currents. As subthreshold currents are orders of magnitude smaller than the currents responsible for the action potential, they are hard to identify and easily overlooked. Discovery of their importance in regulation of excitability opens new avenues for improved therapy for muscle channelopathies and diseases of the neuromuscular junction. ANN NEUROL 2020;87:175-183.
Topics: Animals; Channelopathies; Humans; Ion Channels; Muscles; Myotonia
PubMed: 31725924
DOI: 10.1002/ana.25646 -
Frontiers in Immunology 2022Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease in the central nervous system (CNS). Its pathogenesis is quite complex:... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease in the central nervous system (CNS). Its pathogenesis is quite complex: Accumulated evidence suggests that biochemical signals as well as mechanical stimuli play important roles in MS. In both patients and animal models of MS, brain viscoelasticity is reduced during disease progression. Piezo mechanosensitive channels are recently discovered, and their three-dimensional structure has been solved. Both the membrane dome mechanism and the membrane footprint hypothesis have been proposed to explain their mechanosensitivity. While membrane-mediated forces alone appear to be sufficient to induce Piezo gating, tethers attached to the membrane or to the channel itself also seem to play a role. Current research indicates that Piezo1 channels play a key role in multiple aspects of MS pathogenesis. Activation of Piezo1 channels in axon negatively regulates CNS myelination. in addition, the inhibition of Piezo1 in CD4+ T cells and/or T regulatory cells (Treg) attenuates experimental autoimmune encephalitis (EAE) symptoms. Although more work has to be done to clarify the roles of Piezo1 channels in MS, they might be a promising future drug target for MS treatment.
Topics: Animals; Ion Channel Gating; Ion Channels; Mechanotransduction, Cellular; Models, Animal; Multiple Sclerosis; Neurodegenerative Diseases
PubMed: 36177027
DOI: 10.3389/fimmu.2022.976522 -
Cold Spring Harbor Perspectives in... Nov 2020Influenza A virus AM2 protein is an integral membrane protein that is an ion channel (also known as a viroporin). The channel has 24 extracellular residues, 19 residues... (Review)
Review
Influenza A virus AM2 protein is an integral membrane protein that is an ion channel (also known as a viroporin). The channel has 24 extracellular residues, 19 residues that span the membrane once and acts as both the channel pore and also the membrane anchoring domain, and a 54-residue cytoplasmic tail. The M2 protein has four identical chains linked via two disulfide bonds that form a four-helix bundle that is 10-10 more permeable to protons than Na ions. The M2 channel is activated by low pH, His residue 37 is the pH sensor, and Trp residue 41 is the channel gate. The channel is blocked by the antiviral drug amantadine hydrochloride. The influenza B virus BM2 protein does not have homology with the AM2 channel, but BM2 does have the His proton sensor, Trp gate, and is activated by low pH. It is thought that the AM2 and BM2 proteins have common functions in the influenza A and B virus life cycles. Both BM2 and AM2 also facilitate virus budding. The amphipathic helix in the AM2 cytoplasmic tail has an important role in the assembly of the virus, and functional AM2 protein makes the virus independent of the "endosomal sorting complex required for transport" (ESCRT) complex scission.
Topics: Amantadine; Antiviral Agents; Humans; Influenza A virus; Influenza B virus; Ion Channels
PubMed: 31988204
DOI: 10.1101/cshperspect.a038505 -
Communications Biology Oct 2023Ligand-gated ion channels are formed by three to five subunits that control the opening of the pore in a cooperative fashion. We developed a microfluidic chip-based...
Ligand-gated ion channels are formed by three to five subunits that control the opening of the pore in a cooperative fashion. We developed a microfluidic chip-based technique for studying ion currents and fluorescence signals in either excised membrane patches or whole cells to measure activation and deactivation kinetics of the channels as well as ligand binding and unbinding when using confocal patch-clamp fluorometry. We show how this approach produces in a few seconds either unidirectional concentration-activation relationships at or near equilibrium and, moreover, respective time courses of activation and deactivation for a large number of freely designed steps of the ligand concentration. The short measuring period strongly minimizes the contribution of disturbing superimposing effects such as run-down phenomena and desensitization effects. To validate gating mechanisms, complex kinetic schemes are quantified without the requirement to have data at equilibrium. The new method has potential for functionally analyzing any ligand-gated ion channel and, beyond, also for other receptors.
Topics: Ligand-Gated Ion Channels; Ligands
PubMed: 37783870
DOI: 10.1038/s42003-023-05340-w -
Advanced Science (Weinheim,... Sep 2023The development of bioelectronic neural implant technologies has advanced significantly over the past 5 years, particularly in brain-machine interfaces and electronic...
The development of bioelectronic neural implant technologies has advanced significantly over the past 5 years, particularly in brain-machine interfaces and electronic medicine. However, neuroelectrode-based therapies require invasive neurosurgery and can subject neural tissues to micromotion-induced mechanical shear, leading to chronic inflammation, the formation of a peri-electrode void and the deposition of reactive glial scar tissue. These structures act as physical barriers, hindering electrical signal propagation and reducing neural implant functionality. Although well documented, the mechanisms behind the initiation and progression of these processes are poorly understood. Herein, in silico analysis of micromotion-induced peri-electrode void progression and gliosis is described. Subsequently, ventral mesencephalic cells exposed to milliscale fluid shear stress in vitro exhibited increased expression of gliosis-associated proteins and overexpression of mechanosensitive ion channels PIEZO1 (piezo-type mechanosensitive ion channel component 1) and TRPA1 (transient receptor potential ankyrin 1), effects further confirmed in vivo in a rat model of peri-electrode gliosis. Furthermore, in vitro analysis indicates that chemical inhibition/activation of PIEZO1 affects fluid shear stress mediated astrocyte reactivity in a mitochondrial-dependent manner. Together, the results suggest that mechanosensitive ion channels play a major role in the development of a peri-electrode void and micromotion-induced glial scarring at the peri-electrode region.
Topics: Rats; Animals; Gliosis; Ion Channels; Neuroglia; Astrocytes; Electrodes
PubMed: 37518828
DOI: 10.1002/advs.202301352 -
Proceedings of the National Academy of... Oct 2022We show in the companion paper that the free membrane shape of lipid bilayer vesicles containing the mechanosensitive ion channel Piezo can be predicted, with no free...
We show in the companion paper that the free membrane shape of lipid bilayer vesicles containing the mechanosensitive ion channel Piezo can be predicted, with no free parameters, from membrane elasticity theory together with measurements of the protein geometry and vesicle size [C. A. Haselwandter, Y. R. Guo, Z. Fu, R. MacKinnon, , 10.1073/pnas.2208027119 (2022)]. Here we use these results to determine the force that the Piezo dome exerts on the free membrane and hence, that the free membrane exerts on the Piezo dome, for a range of vesicle sizes. From vesicle shape measurements alone, we thus obtain a force-distortion relationship for the Piezo dome, from which we deduce the Piezo dome's intrinsic radius of curvature, [Formula: see text] nm, and bending stiffness, [Formula: see text], in freestanding lipid bilayer membranes mimicking cell membranes. Applying these estimates to a spherical cap model of Piezo embedded in a lipid bilayer, we suggest that Piezo's intrinsic curvature, surrounding membrane footprint, small stiffness, and large area are the key properties of Piezo that give rise to low-threshold, high-sensitivity mechanical gating.
Topics: Cell Membrane; Elasticity; Ion Channels; Lipid Bilayers; Mechanical Phenomena; Mechanotransduction, Cellular
PubMed: 36166476
DOI: 10.1073/pnas.2208034119 -
Cells Apr 2023Brain channelopathies are a group of neurological disorders that result from genetic mutations affecting ion channels in the brain. Ion channels are specialized proteins... (Review)
Review
Brain channelopathies are a group of neurological disorders that result from genetic mutations affecting ion channels in the brain. Ion channels are specialized proteins that play a crucial role in the electrical activity of nerve cells by controlling the flow of ions such as sodium, potassium, and calcium. When these channels are not functioning properly, they can cause a wide range of neurological symptoms such as seizures, movement disorders, and cognitive impairment. In this context, the axon initial segment (AIS) is the site of action potential initiation in most neurons. This region is characterized by a high density of voltage-gated sodium channels (VGSCs), which are responsible for the rapid depolarization that occurs when the neuron is stimulated. The AIS is also enriched in other ion channels, such as potassium channels, that play a role in shaping the action potential waveform and determining the firing frequency of the neuron. In addition to ion channels, the AIS contains a complex cytoskeletal structure that helps to anchor the channels in place and regulate their function. Therefore, alterations in this complex structure of ion channels, scaffold proteins, and specialized cytoskeleton may also cause brain channelopathies not necessarily associated with ion channel mutations. This review will focus on how the AISs structure, plasticity, and composition alterations may generate changes in action potentials and neuronal dysfunction leading to brain diseases. AIS function alterations may be the consequence of voltage-gated ion channel mutations, but also may be due to ligand-activated channels and receptors and AIS structural and membrane proteins that support the function of voltage-gated ion channels.
Topics: Humans; Axon Initial Segment; Axons; Channelopathies; Ion Channels; Brain; Seizures
PubMed: 37190119
DOI: 10.3390/cells12081210 -
International Journal of Molecular... Mar 2022Human spermatozoan ion channels are specifically distributed in the spermatozoan membrane, contribute to sperm motility, and are associated with male reproductive... (Review)
Review
Human spermatozoan ion channels are specifically distributed in the spermatozoan membrane, contribute to sperm motility, and are associated with male reproductive abnormalities. Calcium, potassium, protons, sodium, and chloride are the main ions that are regulated across this membrane, and their intracellular concentrations are crucial for sperm motility. Fatty acids (FAs) affect sperm quality parameters, reproductive pathologies, male fertility, and regulate ion channel functions in other cells. However, to date the literature is insufficient to draw any conclusions regarding the effects of FAs on human spermatozoan ion channels. Here, we aimed to discern the possible effects of FAs on spermatozoan ion channels and direct guidance for future research. After investigating the effects of FAs on characteristics related to human spermatozoan motility, reproductive pathologies, and the modulation of similar ion channels in other cells by FAs, we extrapolated polyunsaturated FAs (PUFAs) to have the highest potency in modulating sperm ion channels to increase sperm motility. Of the PUFAs, the ω-3 unsaturated fatty acids have the greatest effect. We speculate that saturated and monounsaturated FAs will have little to no effect on sperm ion channel activity, though the possible effects could be opposite to those of the PUFAs, considering the differences between FA structure and behavior.
Topics: Fatty Acids; Humans; Ion Channels; Male; Sodium; Sperm Motility; Spermatozoa
PubMed: 35409078
DOI: 10.3390/ijms23073718