ABSTRACT
The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.
Subject(s)
Cerebellum , Neurons , Retina , Animals , Female , Male , Mice , Cerebellum/metabolism , Cerebellum/blood supply , Cerebellum/cytology , Ion Channels/metabolism , Mice, Inbred C57BL , Neurons/metabolism , Retina/cytology , Retina/metabolism , Retinal Ganglion Cells/metabolism , Retinal Vessels/metabolismABSTRACT
The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal.
Subject(s)
Gastrointestinal Transit , Ion Channels , Mechanotransduction, Cellular , Animals , Humans , Mice , Digestion , Ion Channels/metabolism , Neurons/metabolismABSTRACT
Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.
Subject(s)
Adaptive Immunity/physiology , Immunity, Innate/physiology , Ion Channels/metabolism , Animals , Calcium Channels/genetics , Calcium Channels/metabolism , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Humans , Hypersensitivity/genetics , Hypersensitivity/immunology , Hypersensitivity/metabolism , Immunologic Deficiency Syndromes/drug therapy , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/metabolism , Immunotherapy/methods , Ion Channels/genetics , Lymphocytes/cytology , Lymphocytes/immunology , Lymphocytes/metabolism , Mast Cells/immunology , Mast Cells/metabolism , Molecular Targeted Therapy , Mutation , Signal TransductionABSTRACT
This volume of the Annual Review of Biochemistry contains three reviews on membrane channel proteins: the first by Szczot et al., titled The Form and Function of PIEZO2; the second by Ruprecht & Kunji, titled Structural Mechanism of Transport of Mitochondrial Carriers; and the third by McIlwain et al., titled Membrane Exporters of Fluoride Ion. These reviews provide nice illustrations of just how far evolution has been able to play with the basic helix-bundle architecture of integral membrane proteins to produce membrane channels and transporters of widely different functions.
Subject(s)
Ion Channels/chemistry , Ion Channels/metabolism , Adenosine Diphosphate/metabolism , Adenosine Triphosphate/metabolism , Fluorides/metabolismABSTRACT
Mechanosensation is the ability to detect dynamic mechanical stimuli (e.g., pressure, stretch, and shear stress) and is essential for a wide variety of processes, including our sense of touch on the skin. How touch is detected and transduced at the molecular level has proved to be one of the great mysteries of sensory biology. A major breakthrough occurred in 2010 with the discovery of a family of mechanically gated ion channels that were coined PIEZOs. The last 10 years of investigation have provided a wealth of information about the functional roles and mechanisms of these molecules. Here we focus on PIEZO2, one of the two PIEZO proteins found in humans and other mammals. We review how work at the molecular, cellular, and systems levels over the past decade has transformed our understanding of touch and led to unexpected insights into other types of mechanosensation beyond the skin.
Subject(s)
Drug Discovery/methods , Ion Channels/chemistry , Ion Channels/physiology , Mechanotransduction, Cellular/physiology , Animals , Baroreflex/physiology , Humans , Ion Channels/genetics , Ion Channels/metabolism , Mice , Proprioception/physiology , Stem Cells/physiology , TouchABSTRACT
Microorganisms contend with numerous and unusual chemical threats and have evolved a catalog of resistance mechanisms in response. One particularly ancient, pernicious threat is posed by fluoride ion (F-), a common xenobiotic in natural environments that causes broad-spectrum harm to metabolic pathways. This review focuses on advances in the last ten years toward understanding the microbial response to cytoplasmic accumulation of F-, with a special emphasis on the structure and mechanisms of the proteins that microbes use to export fluoride: the CLCF family of F-/H+ antiporters and the Fluc/FEX family of F- channels.
Subject(s)
Antiporters/chemistry , Antiporters/metabolism , Fluorides/metabolism , Ion Channels/chemistry , Ion Channels/metabolism , Chloride Channels/chemistry , Chloride Channels/metabolism , Cytoplasm/metabolism , Fluorides/toxicity , Ion Transport , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Protein Conformation , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/metabolismABSTRACT
This year's Nobel Prize in Physiology or Medicine was awarded to David Julius and Ardem Patapoutian for "explaining the molecular basis for sensing heat, cold and mechanical force." Their findings capped off a scientific quest to identify the mechanisms within the somatosensory system mediating the detection of internal and external environments.
Subject(s)
Ion Channels/metabolism , Sensation/physiology , Animals , Biomechanical Phenomena , Capsaicin/pharmacology , Humans , Nobel Prize , Touch/physiologyABSTRACT
How are individual cell behaviors coordinated toward invariant large-scale anatomical outcomes in development and regeneration despite unpredictable perturbations? Endogenous distributions of membrane potentials, produced by ion channels and gap junctions, are present across all tissues. These bioelectrical networks process morphogenetic information that controls gene expression, enabling cell collectives to make decisions about large-scale growth and form. Recent progress in the analysis and computational modeling of developmental bioelectric circuits and channelopathies reveals how cellular collectives cooperate toward organ-level structural order. These advances suggest a roadmap for exploiting bioelectric signaling for interventions addressing developmental disorders, regenerative medicine, cancer reprogramming, and synthetic bioengineering.
Subject(s)
Embryonic Development/physiology , Models, Biological , Neoplasms/pathology , Signal Transduction , Animals , Electrophysiological Phenomena , Humans , Ion Channels/metabolism , Neoplasms/metabolism , Regenerative MedicineABSTRACT
Mammals use glabrous (hairless) skin of their hands and feet to navigate and manipulate their environment. Cortical maps of the body surface across species contain disproportionately large numbers of neurons dedicated to glabrous skin sensation, in part reflecting a higher density of mechanoreceptors that innervate these skin regions. Here, we find that disproportionate representation of glabrous skin emerges over postnatal development at the first synapse between peripheral mechanoreceptors and their central targets in the brainstem. Mechanoreceptor synapses undergo developmental refinement that depends on proximity of their terminals to glabrous skin, such that those innervating glabrous skin make synaptic connections that expand their central representation. In mice incapable of sensing gentle touch, mechanoreceptors innervating glabrous skin still make more powerful synapses in the brainstem. We propose that the skin region a mechanoreceptor innervates controls the developmental refinement of its central synapses to shape the representation of touch in the brain.
Subject(s)
Brain Stem/metabolism , Mechanoreceptors/metabolism , Synapses/metabolism , Touch Perception/physiology , Action Potentials/physiology , Animals , Animals, Newborn , Axons/metabolism , Ion Channels/metabolism , Mice, Knockout , Neurons/metabolism , Optical Imaging , Optogenetics , Skin/innervationABSTRACT
Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%-5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.
Subject(s)
Ion Channels/metabolism , Iron/metabolism , Black or African American , Aging/metabolism , Alleles , Animals , Cohort Studies , Erythrocyte Count , Erythropoiesis , Gain of Function Mutation/genetics , Hepatocytes/metabolism , Hepcidins/blood , Hepcidins/metabolism , Humans , Iron/blood , Iron Overload/metabolism , Macrophages/metabolism , Mechanotransduction, Cellular , Mice, Inbred C57BL , Phagocytosis , Phenotype , Stress, PhysiologicalABSTRACT
Neurons are frequently classified into distinct types on the basis of structural, physiological, or genetic attributes. To better constrain the definition of neuronal cell types, we characterized the transcriptomes and intrinsic physiological properties of over 4,200 mouse visual cortical GABAergic interneurons and reconstructed the local morphologies of 517 of those neurons. We find that most transcriptomic types (t-types) occupy specific laminar positions within visual cortex, and, for most types, the cells mapping to a t-type exhibit consistent electrophysiological and morphological properties. These properties display both discrete and continuous variation among t-types. Through multimodal integrated analysis, we define 28 met-types that have congruent morphological, electrophysiological, and transcriptomic properties and robust mutual predictability. We identify layer-specific axon innervation pattern as a defining feature distinguishing different met-types. These met-types represent a unified definition of cortical GABAergic interneuron types, providing a systematic framework to capture existing knowledge and bridge future analyses across different modalities.
Subject(s)
Cerebral Cortex/cytology , Electrophysiological Phenomena , GABAergic Neurons/cytology , GABAergic Neurons/metabolism , Transcriptome/genetics , Animals , Female , Gene Expression Profiling , Hippocampus/physiology , Ion Channels/metabolism , Male , Mice, Inbred C57BL , Nerve Tissue Proteins/metabolismABSTRACT
Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.
Subject(s)
Bone and Bones/metabolism , Colon/metabolism , Gastrointestinal Motility/genetics , Ion Channels/metabolism , RNA/metabolism , Serotonin/biosynthesis , Serotonin/metabolism , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Bone and Bones/cytology , Calcium/metabolism , Colitis/genetics , Colitis/metabolism , Colitis/prevention & control , Colon/physiology , Feces/chemistry , Female , Gastrointestinal Motility/physiology , HEK293 Cells , Humans , Immunohistochemistry , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Ion Channels/genetics , Ligands , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microbiota/drug effects , Myeloid Differentiation Factor 88/metabolism , Osteoclasts/metabolism , Pyrazines/pharmacology , RNA/pharmacology , Ribonuclease, Pancreatic/administration & dosage , Serotonin/blood , Serotonin/deficiency , Thiadiazoles/pharmacologyABSTRACT
The volume-regulated anion channel (VRAC) is formed by LRRC8 proteins and is responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling. Besides chloride, VRAC transports other molecules, for example, immunomodulatory cyclic dinucleotides (CDNs) including 2'3'cGAMP. Here, we identify LRRC8C as a critical component of VRAC in T cells, where its deletion abolishes VRAC currents and RVD. T cells of Lrrc8c-/- mice have increased cell cycle progression, proliferation, survival, Ca2+ influx and cytokine production-a phenotype associated with downmodulation of p53 signaling. Mechanistically, LRRC8C mediates the transport of 2'3'cGAMP in T cells, resulting in STING and p53 activation. Inhibition of STING recapitulates the phenotype of LRRC8C-deficient T cells, whereas overexpression of p53 inhibits their enhanced T cell function. Lrrc8c-/- mice have exacerbated T cell-dependent immune responses, including immunity to influenza A virus infection and experimental autoimmune encephalomyelitis. Our results identify cGAMP uptake through LRRC8C and STING-p53 signaling as a new inhibitory signaling pathway in T cells and adaptive immunity.
Subject(s)
Anions/metabolism , Dinucleoside Phosphates/metabolism , Ion Channels/metabolism , Membrane Proteins/metabolism , T-Lymphocytes/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Calcium/metabolism , Female , Mice , Mice, Inbred C57BL , Nucleotides, Cyclic/metabolism , Signal Transduction/physiologyABSTRACT
Animals must respond to the ingestion of food by generating adaptive behaviors, but the role of gut-brain signaling in behavioral regulation is poorly understood. Here, we identify conserved ion channels in an enteric serotonergic neuron that mediate its responses to food ingestion and decipher how these responses drive changes in foraging behavior. We show that the C. elegans serotonergic neuron NSM acts as an enteric sensory neuron that acutely detects food ingestion. We identify the novel and conserved acid-sensing ion channels (ASICs) DEL-7 and DEL-3 as NSM-enriched channels required for feeding-dependent NSM activity, which in turn drives slow locomotion while animals feed. Point mutations that alter the DEL-7 channel change NSM dynamics and associated behavioral dynamics of the organism. This study provides causal links between food ingestion, molecular and physiological properties of an enteric serotonergic neuron, and adaptive feeding behaviors, yielding a new view of how enteric neurons control behavior.
Subject(s)
Acid Sensing Ion Channels/metabolism , Enteric Nervous System/metabolism , Feeding Behavior/physiology , Acid Sensing Ion Channels/physiology , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/physiology , Caenorhabditis elegans Proteins/metabolism , Enteric Nervous System/physiology , Food , Ion Channels/metabolism , Ion Channels/physiology , Locomotion , Neurons/metabolism , Sensory Receptor Cells/metabolism , Serotonergic Neurons/metabolism , Serotonergic Neurons/physiology , Serotonin , Signal TransductionABSTRACT
The biophysical features of neurons shape information processing in the brain. Cortical neurons are larger in humans than in other species, but it is unclear how their size affects synaptic integration. Here, we perform direct electrical recordings from human dendrites and report enhanced electrical compartmentalization in layer 5 pyramidal neurons. Compared to rat dendrites, distal human dendrites provide limited excitation to the soma, even in the presence of dendritic spikes. Human somas also exhibit less bursting due to reduced recruitment of dendritic electrogenesis. Finally, we find that decreased ion channel densities result in higher input resistance and underlie the lower coupling of human dendrites. We conclude that the increased length of human neurons alters their input-output properties, which will impact cortical computation. VIDEO ABSTRACT.
Subject(s)
Dendrites/physiology , Pyramidal Cells/physiology , Action Potentials , Adult , Animals , Female , Humans , Ion Channels/metabolism , Male , Pyramidal Cells/cytology , Rats , Rats, Sprague-Dawley , Species Specificity , Synaptic PotentialsABSTRACT
The fluid-mosaic model posits a liquid-like plasma membrane, which can flow in response to tension gradients. It is widely assumed that membrane flow transmits local changes in membrane tension across the cell in milliseconds, mediating long-range signaling. Here, we show that propagation of membrane tension occurs quickly in cell-attached blebs but is largely suppressed in intact cells. The failure of tension to propagate in cells is explained by a fluid dynamical model that incorporates the flow resistance from cytoskeleton-bound transmembrane proteins. Perturbations to tension propagate diffusively, with a diffusion coefficient Dσ â¼0.024 µm2/s in HeLa cells. In primary endothelial cells, local increases in membrane tension lead only to local activation of mechanosensitive ion channels and to local vesicle fusion. Thus, membrane tension is not a mediator of long-range intracellular signaling, but local variations in tension mediate distinct processes in sub-cellular domains.
Subject(s)
Cell Membrane/metabolism , Cytoskeleton/metabolism , Ion Channels/metabolism , Models, Biological , Signal Transduction/physiology , Animals , Dogs , HeLa Cells , Humans , Madin Darby Canine Kidney Cells , Mice , NIH 3T3 Cells , RatsABSTRACT
Ion channel families are broadly classified into three types according to their major mechanisms of activation. This SnapShot highlights features of these three classes and conveys general modes of channel regulation. To view this SnapShot, open or download the PDF.
Subject(s)
Ion Channel Gating , Ion Channels/genetics , Ion Channels/metabolism , Animals , Cell Membrane/metabolism , Gene Expression Regulation , Humans , Ion Channels/chemistryABSTRACT
Germination is the process by which spores emerge from dormancy. Although spores can remain dormant for decades, the study of germination is an active field of research. In this issue of Genes & Development, Gao and colleagues (pp. 31-45) address a perplexing question: How can a dormant spore initiate germination in response to environmental cues? Three distinct complexes are involved: GerA, a germinant-gated ion channel; 5AF/FigP, a second ion channel required for amplification; and SpoVA, a channel for dipicolinic acid (DPA). DPA release is followed by rehydration of the spore core, thus allowing the resumption of metabolic activity.
Subject(s)
Bacterial Proteins , Spores, Bacterial , Spores, Bacterial/genetics , Spores, Bacterial/metabolism , Bacterial Proteins/metabolism , Spores/metabolism , Ion Channels/metabolism , Bacillus subtilis/metabolismABSTRACT
Bacterial spores can remain dormant for decades yet rapidly germinate and resume growth in response to nutrients. GerA family receptors that sense and respond to these signals have recently been shown to oligomerize into nutrient-gated ion channels. Ion release initiates exit from dormancy. Here, we report that a distinct ion channel, composed of SpoVAF (5AF) and its newly discovered partner protein, YqhR (FigP), amplifies the response. At high germinant concentrations, 5AF/FigP accelerate germination; at low concentrations, this complex becomes critical for exit from dormancy. 5AF is homologous to the channel-forming subunit of GerA family receptors and is predicted to oligomerize around a central pore. 5AF mutations predicted to widen the channel cause constitutive germination during spore formation and membrane depolarization in vegetative cells. Narrow-channel mutants are impaired in germination. A screen for suppressors of a constitutively germinating 5AF mutant identified FigP as an essential cofactor of 5AF activity. We demonstrate that 5AF and FigP interact and colocalize with GerA family receptors in spores. Finally, we show that 5AF/FigP accelerate germination in B. subtilis spores that have nutrient receptors from another species. Our data support a model in which nutrient-triggered ion release by GerA family receptors activates 5AF/FigP ion release, amplifying the response to germinant signals.
Subject(s)
Bacillus subtilis , Membrane Proteins , Bacillus subtilis/genetics , Bacillus subtilis/metabolism , Membrane Proteins/genetics , Spores, Bacterial/genetics , Spores, Bacterial/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Ion Channels/genetics , Ion Channels/metabolismABSTRACT
The endomembrane system consists of organellar membranes in the biosynthetic pathway [endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles] as well as those in the degradative pathway (early endosomes, macropinosomes, phagosomes, autophagosomes, late endosomes, and lysosomes). These endomembrane organelles/vesicles work together to synthesize, modify, package, transport, and degrade proteins, carbohydrates, and lipids, regulating the balance between cellular anabolism and catabolism. Large ion concentration gradients exist across endomembranes: Ca2+ gradients for most endomembrane organelles and H+ gradients for the acidic compartments. Ion (Na+, K+, H+, Ca2+, and Cl-) channels on the organellar membranes control ion flux in response to cellular cues, allowing rapid informational exchange between the cytosol and organelle lumen. Recent advances in organelle proteomics, organellar electrophysiology, and luminal and juxtaorganellar ion imaging have led to molecular identification and functional characterization of about two dozen endomembrane ion channels. For example, whereas IP3R1-3 channels mediate Ca2+ release from the ER in response to neurotransmitter and hormone stimulation, TRPML1-3 and TMEM175 channels mediate lysosomal Ca2+ and H+ release, respectively, in response to nutritional and trafficking cues. This review aims to summarize the current understanding of these endomembrane channels, with a focus on their subcellular localizations, ion permeation properties, gating mechanisms, cell biological functions, and disease relevance.