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Cell Reports Jul 2023Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We...
Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We find that mice with prenatal deletion in cortical excitatory neurons and oligodendrocytes (Ank2:Emx1-Cre), but not with adolescent deletion in forebrain excitatory neurons (Ank2:CaMKIIα-Cre), display severe spontaneous seizures, increased mortality, hyperactivity, and social deficits. Calcium imaging of cortical slices from Ank2:Emx1-Cre mice shows increased neuronal calcium event amplitude and frequency, along with network hyperexcitability and hypersynchrony. Quantitative proteomic analysis of cortical synaptic membranes reveals upregulation of dendritic spine plasticity-regulatory proteins and downregulation of intermediate filaments. Characterization of the ankyrin-B interactome identifies interactors associated with autism and epilepsy risk factors and synaptic proteins. The AMPA receptor antagonist, perampanel, restores cortical neuronal activity and partially rescues survival in Ank2:Emx1-Cre mice. Our findings suggest that synaptic proteome alterations resulting from Ank2 deletion impair neuronal activity and synchrony, leading to NDDs-related behavioral impairments.
Topics: Animals; Mice; Ankyrins; Calcium; Phenotype; Prosencephalon; Proteome; Proteomics; Seizures; Mice, Knockout
PubMed: 37428632
DOI: 10.1016/j.celrep.2023.112784 -
Physiological Reviews Jul 2001The spectrin-based membrane skeleton of the humble mammalian erythrocyte has provided biologists with a set of interacting proteins with diverse roles in organization... (Review)
Review
The spectrin-based membrane skeleton of the humble mammalian erythrocyte has provided biologists with a set of interacting proteins with diverse roles in organization and survival of cells in metazoan organisms. This review deals with the molecular physiology of spectrin, ankyrin, which links spectrin to the anion exchanger, and two spectrin-associated proteins that promote spectrin interactions with actin: adducin and protein 4.1. The lack of essential functions for these proteins in generic cells grown in culture and the absence of their genes in the yeast genome have, until recently, limited advances in understanding their roles outside of erythrocytes. However, completion of the genomes of simple metazoans and application of homologous recombination in mice now are providing the first glimpses of the full scope of physiological roles for spectrin, ankyrin, and their associated proteins. These functions now include targeting of ion channels and cell adhesion molecules to specialized compartments within the plasma membrane and endoplasmic reticulum of striated muscle and the nervous system, mechanical stabilization at the tissue level based on transcellular protein assemblies, participation in epithelial morphogenesis, and orientation of mitotic spindles in asymmetric cell divisions. These studies, in addition to stretching the erythrocyte paradigm beyond recognition, also are revealing novel cellular pathways essential for metazoan life. Examples are ankyrin-dependent targeting of proteins to excitable membrane domains in the plasma membrane and the Ca(2+) homeostasis compartment of the endoplasmic reticulum. Exciting questions for the future relate to the molecular basis for these pathways and their roles in a clinical context, either as the basis for disease or more positively as therapeutic targets.
Topics: Amino Acid Sequence; Animals; Anion Exchange Protein 1, Erythrocyte; Ankyrins; Erythrocyte Membrane; Humans; Models, Molecular; Molecular Sequence Data; Sodium Channels; Spectrin; Structure-Activity Relationship
PubMed: 11427698
DOI: 10.1152/physrev.2001.81.3.1353 -
Cellular and Molecular Life Sciences :... Aug 2010The interaction of ankyrin and spectrin yields the major anchor between the membrane skeleton and the lipid bilayer. It is critical for red cell deformability and... (Review)
Review
The interaction of ankyrin and spectrin yields the major anchor between the membrane skeleton and the lipid bilayer. It is critical for red cell deformability and stability, and it is also involved in the cellular localization of several proteins, in cell differentiation, and in neuron activity. Therefore, its nature is of great interest, and recently, several researchers have had varying degrees of success in elucidating the structural basis of ankyrin-spectrin recognition. In this short paper, we briefly summarize the data obtained and compare the resulting conclusions.
Topics: Ankyrins; Erythrocyte Deformability; Erythrocytes; Glucose Transporter Type 1; Glycophorins; Humans; Intracellular Signaling Peptides and Proteins; Kinetics; Lipid Bilayers; Models, Biological; Spectrin
PubMed: 20411297
DOI: 10.1007/s00018-010-0371-1 -
Cold Spring Harbor Perspectives in... Dec 2009Nodes of Ranvier and axon initial segments of myelinated nerves, sites of cell-cell contact in early embryos and epithelial cells, and neuromuscular junctions of... (Review)
Review
Nodes of Ranvier and axon initial segments of myelinated nerves, sites of cell-cell contact in early embryos and epithelial cells, and neuromuscular junctions of skeletal muscle all perform physiological functions that depend on clustering of functionally related but structurally diverse ion transporters and cell adhesion molecules within microdomains of the plasma membrane. These specialized cell surface domains appeared at different times in metazoan evolution, involve a variety of cell types, and are populated by distinct membrane-spanning proteins. Nevertheless, recent work has shown that these domains all share on their cytoplasmic surfaces a membrane skeleton comprised of members of the ankyrin and spectrin families. This review will summarize basic features of ankyrins and spectrins, and will discuss emerging evidence that these proteins are key players in a conserved mechanism responsible for assembly and maintenance of physiologically important domains on the surfaces of diverse cells.
Topics: Animals; Ankyrins; Cell Communication; Cell Membrane; Intercellular Junctions; Spectrin
PubMed: 20457566
DOI: 10.1101/cshperspect.a003012 -
Current Opinion in Neurobiology Aug 2016Neurons are organized and connected into functional circuits by axons that conduct action potentials. Many vertebrate axons are myelinated and further subdivided into... (Review)
Review
Neurons are organized and connected into functional circuits by axons that conduct action potentials. Many vertebrate axons are myelinated and further subdivided into excitable domains that include the axon initial segment (AIS) and nodes of Ranvier. Nodes of Ranvier regenerate and propagate action potentials, while AIS regulate action potential initiation and neuronal polarity. Two distinct cytoskeletons control axon structure and function: 1) a submembranous ankyrin/spectrin cytoskeleton that clusters ion channels and provides mechanical support, and 2) a microtubule-based cytoskeleton that controls selective trafficking of dendritic and axonal cargoes. Here, we review recent studies that provide significant additional insight into the cytoskeleton-dependent mechanisms controlling the functional organization of axons.
Topics: Animals; Ankyrins; Axons; Cytoskeleton; Neurons; Ranvier's Nodes
PubMed: 27203619
DOI: 10.1016/j.conb.2016.05.001 -
Seminars in Cell & Developmental Biology Apr 2011The coordinate activities of ion channels and transporters regulate myocyte membrane excitability and normal cardiac function. Dysfunction in cardiac ion channel and... (Review)
Review
The coordinate activities of ion channels and transporters regulate myocyte membrane excitability and normal cardiac function. Dysfunction in cardiac ion channel and transporter function may result in cardiac arrhythmias and sudden cardiac death. While the past fifteen years have linked defects in ion channel biophysical properties with human disease, more recent findings illustrate that ion channel and transporter localization within cardiomyocytes is equally critical for normal membrane excitability and tissue function. Ankyrins are a family of multifunctional adapter proteins required for the expression, membrane localization, and regulation of select cardiac ion channels and transporters. Notably, loss of ankyrin expression in mice, and ankyrin loss-of-function in humans is now associated with defects in myocyte excitability and cardiac physiology. Here, we provide an overview of the roles of ankyrin polypeptides in cardiac physiology, as well as review other recently identified pathways required for the membrane expression and regulation of key cardiac ion channels and transporters.
Topics: Animals; Ankyrins; Biological Transport; Humans; Intracellular Space; Ion Channels; Membrane Transport Proteins; Myocytes, Cardiac
PubMed: 20934528
DOI: 10.1016/j.semcdb.2010.09.013 -
Current Opinion in Cell Biology Aug 1998Recent discoveries reveal a Golgi-centric spectrin-ankyrin skeleton required for Golgi integrity and anterograde protein trafficking. Identification of specific... (Review)
Review
Recent discoveries reveal a Golgi-centric spectrin-ankyrin skeleton required for Golgi integrity and anterograde protein trafficking. Identification of specific functional domains in spectrin that mediate its association with motor proteins and the Golgi complex has allowed novel insights into the structure and function of the secretory pathway, and into how this process is controlled by ADP-ribosylation factor and phosphoinositides. Alternative models of Golgi spectrin function that have been recently proposed are reviewed.
Topics: ADP-Ribosylation Factors; Ankyrins; Biological Transport; Cell Compartmentation; Cell Membrane; GTP-Binding Proteins; Golgi Apparatus; Phosphatidylinositols; Spectrin
PubMed: 9719877
DOI: 10.1016/s0955-0674(98)80071-9 -
Cells Aug 2021The 20-60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural... (Review)
Review
The 20-60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural properties regulated by the crucial protein, ankyrin-G. The AIS contains a high density of Na channels relative to the cell body, which allows low thresholds for the initiation of action potential (AP). Molecular and physiological studies have shown that the AIS is also a key domain for the control of neuronal excitability by homeostatic mechanisms. The AIS has high plasticity in normal developmental processes and pathological activities, such as injury, neurodegeneration, and neurodevelopmental disorders (NDDs). In the first half of this review, we provide an overview of the molecular, structural, and ion-channel characteristics of AIS, AIS regulation through axo-axonic synapses, and axo-glial interactions. In the second half, to understand the relationship between NDDs and AIS, we discuss the activity-dependent plasticity of AIS, the human mutation of AIS regulatory genes, and the pathophysiological role of an abnormal AIS in NDD model animals and patients. We propose that the AIS may provide a potentially valuable structural biomarker in response to abnormal network activity in vivo as well as a new treatment concept at the neural circuit level.
Topics: Action Potentials; Ankyrins; Axon Initial Segment; Humans; Ion Channels; Mutation; Neurodevelopmental Disorders; Neuroglia; Neuronal Plasticity; Spectrin; Synapses
PubMed: 34440880
DOI: 10.3390/cells10082110 -
Journal of Cellular and Molecular... 2009In eukaryotic cells, ankyrins serve as adaptor proteins that link membrane proteins to the underlying cytoskeleton. These adaptor proteins form protein complexes... (Review)
Review
In eukaryotic cells, ankyrins serve as adaptor proteins that link membrane proteins to the underlying cytoskeleton. These adaptor proteins form protein complexes consisting of integral membrane proteins, signalling molecules and cytoskeletal components. With their modular architecture and ability to interact with many proteins, ankyrins organize and stabilize these protein networks, thereby establishing the infrastructure of membrane domains with specialized functions. To this end, ankyrin collaborates with a number of proteins including cytoskeletal proteins, cell adhesion molecules and large structural proteins. This review addresses the targeting and stabilization of protein networks related to ankyrin interactions with the cytoskeletal protein beta-spectrin, L1-cell adhesion molecules and the large myofibrillar protein obscurin. The significance of these interactions for differential targeting of cardiac proteins and neuronal membrane formation is also presented. Finally, this review concludes with a discussion about ankyrin dysfunction in human diseases such as haemolytic anaemia, cardiac arrhythmia and neurological disorders.
Topics: Animals; Ankyrins; Cell Membrane; Disease; Humans; Protein Binding; Protein Stability
PubMed: 19840192
DOI: 10.1111/j.1582-4934.2009.00943.x -
Cytoskeleton (Hoboken, N.J.) Mar 2020The highly polarized, typically very long, and nonmitotic nature of neurons present them with unique challenges in the maintenance of their homeostasis. This... (Review)
Review
The highly polarized, typically very long, and nonmitotic nature of neurons present them with unique challenges in the maintenance of their homeostasis. This architectural complexity serves a rich and tightly controlled set of functions that enables their fast communication with neighboring cells and endows them with exquisite plasticity. The submembrane neuronal cytoskeleton occupies a pivotal position in orchestrating the structural patterning that determines local and long-range subcellular specialization, membrane dynamics, and a wide range of signaling events. At its center is the partnership between ankyrins and spectrins, which self-assemble with both remarkable long-range regularity and micro- and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins. To accomplish these generally conserved, but often functionally divergent and spatially diverse, roles these partners use a combinatorial program of a couple of dozens interacting family members, whose code is not fully unraveled. In a departure from their scaffolding roles, ankyrins and spectrins also enable the delivery of material to the plasma membrane by facilitating intracellular transport. Thus, it is unsurprising that deficits in ankyrins and spectrins underlie several neurodevelopmental, neurodegenerative, and psychiatric disorders. Here, I summarize key aspects of the biology of spectrins and ankyrins in the mammalian neuron and provide a snapshot of the latest advances in decoding their roles in the nervous system.
Topics: Ankyrins; Biological Transport; Neurons; Spectrin
PubMed: 32034889
DOI: 10.1002/cm.21602