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      Ankyrin protein networks in membrane formation and stabilization

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          Abstract

          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 β-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.

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          Most cited references124

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          A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

          Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.
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            AnkyrinG Is Required for Clustering of Voltage-gated Na Channels at Axon Initial Segments and for Normal Action Potential Firing

            Voltage-gated sodium channels (NaCh) are colocalized with isoforms of the membrane-skeletal protein ankyrinG at axon initial segments, nodes of Ranvier, and postsynaptic folds of the mammalian neuromuscular junction. The role of ankyrinG in directing NaCh localization to axon initial segments was evaluated by region-specific knockout of ankyrinG in the mouse cerebellum. Mutant mice exhibited a progressive ataxia beginning around postnatal day P16 and subsequent loss of Purkinje neurons. In mutant mouse cerebella, NaCh were absent from axon initial segments of granule cell neurons, and Purkinje cells showed deficiencies in their ability to initiate action potentials and support rapid, repetitive firing. Neurofascin, a member of the L1CAM family of ankyrin-binding cell adhesion molecules, also exhibited impaired localization to initial segments of Purkinje cell neurons. These results demonstrate that ankyrinG is essential for clustering NaCh and neurofascin at axon initial segments and is required for physiological levels of sodium channel activity.
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              Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.

              Mutations in ion channels involved in the generation and termination of action potentials constitute a family of molecular defects that underlie fatal cardiac arrhythmias in inherited long-QT syndrome. We report here that a loss-of-function (E1425G) mutation in ankyrin-B (also known as ankyrin 2), a member of a family of versatile membrane adapters, causes dominantly inherited type 4 long-QT cardiac arrhythmia in humans. Mice heterozygous for a null mutation in ankyrin-B are haploinsufficient and display arrhythmia similar to humans. Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level. Ankyrin-B mutation also leads to altered Ca2+ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia. Thus, we identify a new mechanism for cardiac arrhythmia due to abnormal coordination of multiple functionally related ion channels and transporters.
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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                jcmm
                Journal of Cellular and Molecular Medicine
                John Wiley & Sons, Ltd (Chichester, UK )
                1582-1838
                1582-4934
                Nov-Dec 2009
                16 October 2009
                : 13
                : 11-12
                : 4364-4376
                Affiliations
                [a ]Department of Internal Medicine, University of Iowa Carver College of Medicine Iowa City, IA, USA
                [b ]Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine Iowa City, IA, USA
                Author notes
                * Correspondence to: Shane R. CUNHA, Department of Internal Medicine, University of Iowa Carver College of Medicine, 285 Newton Rd, CBRB 2283, Iowa City, IA 52242, USA. Tel.: +1 319 335-9679 Fax: +1 319 353-5552 E-mail: shane-cunha@ 123456uiowa.edu
                Article
                10.1111/j.1582-4934.2009.00943.x
                4515052
                19840192
                8e8def1f-4298-4edf-a47a-b0d5b0f1bd3f
                © 2009 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                History
                : 03 July 2009
                : 09 September 2009
                Categories
                Reviews

                Molecular medicine
                ankyrin,β-spectrin,obscurin,l1-cam,cardiomyocyte,axon initial segment,node of ranvier
                Molecular medicine
                ankyrin, β-spectrin, obscurin, l1-cam, cardiomyocyte, axon initial segment, node of ranvier

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