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Channels (Austin, Tex.) Dec 2024Voltage-gated sodium (Na) channels govern membrane excitability by initiating and propagating action potentials. Consistent with their physiological significance,... (Review)
Review
Voltage-gated sodium (Na) channels govern membrane excitability by initiating and propagating action potentials. Consistent with their physiological significance, dysfunction, or mutations in these channels are associated with various channelopathies. Na channels are thereby major targets for various clinical and investigational drugs. In addition, a large number of natural toxins, both small molecules and peptides, can bind to Na channels and modulate their functions. Technological breakthrough in cryo-electron microscopy (cryo-EM) has enabled the determination of high-resolution structures of eukaryotic and eventually human Na channels, alone or in complex with auxiliary subunits, toxins, and drugs. These studies have not only advanced our comprehension of channel architecture and working mechanisms but also afforded unprecedented clarity to the molecular basis for the binding and mechanism of action (MOA) of prototypical drugs and toxins. In this review, we will provide an overview of the recent advances in structural pharmacology of Na channels, encompassing the structural map for ligand binding on Na channels. These findings have established a vital groundwork for future drug development.
Topics: Humans; Voltage-Gated Sodium Channels; Cryoelectron Microscopy; Action Potentials; Peptides; Sodium
PubMed: 38033122
DOI: 10.1080/19336950.2023.2287832 -
Physiological Reviews Jan 2024Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of a large repertoire of membrane proteins, especially ion channels.... (Review)
Review
Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of a large repertoire of membrane proteins, especially ion channels. Unique complements of coexpressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intracellular concentrations of ions, mainly Na, K, and Cl, and their passive permeation across the cell membrane through leak ion channels. Indeed, dysregulation of RMP causes significant effects on cellular excitability. This review describes the molecular and physiological properties of the Na leak channel NALCN, which associates with its accessory subunits UNC-79, UNC-80, and NLF-1/FAM155 to conduct depolarizing background Na currents in various excitable cell types, especially neurons. Studies of animal models clearly demonstrate that NALCN contributes to fundamental physiological processes in the nervous system including the control of respiratory rhythm, circadian rhythm, sleep, and locomotor behavior. Furthermore, dysfunction of NALCN and its subunits is associated with severe pathological states in humans. The critical involvement of NALCN in physiology is now well established, but its study has been hampered by the lack of specific drugs that can block or agonize NALCN currents in vitro and in vivo. Molecular tools and animal models are now available to accelerate our understanding of how NALCN contributes to key physiological functions and the development of novel therapies for NALCN channelopathies.
Topics: Humans; Animals; Sodium Channels; Ion Channels; Membrane Potentials; Neurons; Sodium; Membrane Proteins
PubMed: 37615954
DOI: 10.1152/physrev.00014.2022 -
Advanced Science (Weinheim,... Sep 2023Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis;...
Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis; however, therapeutic choices for this condition remain controversial. Mesenchymal stem cells (MSCs) are a family member of stem cells with immunomodulatory and anti-inflammatory capabilities that can mitigate damage in experimental pancreatitis. Here, it is shown that MSCs deliver hypoxia-treated functional mitochondria to damaged pancreatic acinar cells (PACs) via extracellular vesicles (EVs), which reverse the metabolic function of PACs, maintain ATP supply, and exhibit an excellent injury-inhibiting effect. Mechanistically, hypoxia inhibits superoxide accumulation in the mitochondria of MSCs and upregulates the membrane potential, which is internalized into PACs via EVs, thus, remodeling the metabolic state. In addition, cargocytes constructed via stem cell denucleation as mitochondrial vectors are shown to exert similar therapeutic effects to MSCs. These findings reveal an important mechanism underlying the role of mitochondria in MSC therapy and offer the possibility of applying mitochondrial therapy to patients with severe acute pancreatitis.
Topics: Acinar Cells; Acute Disease; Adenosine Triphosphate; Bile Acids and Salts; Cell Hypoxia; Cellular Reprogramming; Extracellular Vesicles; Membrane Potential, Mitochondrial; Mesenchymal Stem Cells; Mitochondria; Mitochondrial Permeability Transition Pore; Pancreas; Pancreatitis; Paracrine Communication; Superoxides; Umbilical Cord; Humans
PubMed: 37409821
DOI: 10.1002/advs.202207691 -
Cell Dec 2023The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific...
The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. Molecularly, LRRC37B binds to the secreted ligand FGF13A and to the voltage-gated sodium channel (Nav) β-subunit SCN1B. LRRC37B concentrates inhibitory effects of FGF13A on Nav channel function, thereby reducing excitability, specifically at the AIS level. Electrophysiological recordings in adult human cortical slices reveal lower neuronal excitability in human CPNs expressing LRRC37B. LRRC37B thus acts as a species-specific modifier of human neuron excitability, linking human genome and cell evolution, with important implications for human brain function and diseases.
Topics: Animals; Humans; Mice; Action Potentials; Axons; Neurons; Pyramidal Cells; Voltage-Gated Sodium Channels
PubMed: 38134874
DOI: 10.1016/j.cell.2023.11.028 -
Nature Communications Oct 2023The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by...
The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid phosphatidylinositol 4,5-bisphosphate (PIP), and HN37 (pynegabine), an antiepileptic drug in the clinical trial, in an either closed or open conformation. The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms on the KCNQ2 channel. These structures may guide the development of antiepileptic drugs and analgesics that target KCNQ2.
Topics: Humans; Anticonvulsants; Cryoelectron Microscopy; Ligands; Membrane Potentials; Analgesics; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel
PubMed: 37857637
DOI: 10.1038/s41467-023-42416-x -
MIRO-1 interacts with VDAC-1 to regulate mitochondrial membrane potential in Caenorhabditis elegans.EMBO Reports Aug 2023Precise regulation of mitochondrial fusion and fission is essential for cellular activity and animal development. Imbalances between these processes can lead to...
Precise regulation of mitochondrial fusion and fission is essential for cellular activity and animal development. Imbalances between these processes can lead to fragmentation and loss of normal membrane potential in individual mitochondria. In this study, we show that MIRO-1 is stochastically elevated in individual fragmented mitochondria and is required for maintaining mitochondrial membrane potential. We further observe a higher level of membrane potential in fragmented mitochondria in fzo-1 mutants and wounded animals. Moreover, MIRO-1 interacts with VDAC-1, a crucial mitochondrial ion channel located in the outer mitochondrial membrane, and this interaction depends on the residues E473 of MIRO-1 and K163 of VDAC-1. The E473G point mutation disrupts their interaction, resulting in a reduction of the mitochondrial membrane potential. Our findings suggest that MIRO-1 regulates membrane potential and maintains mitochondrial activity and animal health by interacting with VDAC-1. This study provides insight into the mechanisms underlying the stochastic maintenance of membrane potential in fragmented mitochondria.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membranes; Voltage-Dependent Anion Channel 1
PubMed: 37306041
DOI: 10.15252/embr.202256297 -
Annual Review of Physiology Feb 2024A handful of biological proton-selective ion channels exist. Some open at positive or negative membrane potentials, others open at low or high pH, and some are light... (Review)
Review
A handful of biological proton-selective ion channels exist. Some open at positive or negative membrane potentials, others open at low or high pH, and some are light activated. This review focuses on common features that result from the unique properties of protons. Proton conduction through water or proteins differs qualitatively from that of all other ions. Extraordinary proton selectivity is needed to ensure that protons permeate and other ions do not. Proton selectivity arises from a proton pathway comprising a hydrogen-bonded chain that typically includes at least one titratable amino acid side chain. The enormously diverse functions of proton channels in disparate regions of the phylogenetic tree can be summarized by considering the chemical and electrical consequences of proton flux across membranes. This review discusses examples of cells in which proton efflux serves to increase pH, decrease pH, control the membrane potential, generate action potentials, or compensate transmembrane movement of electrical charge.
Topics: Humans; Protons; Ion Channel Gating; Hydrogen-Ion Concentration; Phylogeny; Ion Channels
PubMed: 37931166
DOI: 10.1146/annurev-physiol-042222-023242 -
International Journal of Molecular... Sep 2023Signals of nerve impulses are transmitted to excitatory cells to induce the action of organs via the activation of Ca entry through voltage-gated Ca channels (VGCC),...
Signals of nerve impulses are transmitted to excitatory cells to induce the action of organs via the activation of Ca entry through voltage-gated Ca channels (VGCC), which are classified based on their activation threshold into high- and low-voltage activated channels, expressed specifically for each organ [...].
Topics: Calcium Channels; Calcium-Binding Proteins; Action Potentials
PubMed: 37762560
DOI: 10.3390/ijms241814257