Faculty Opinions recommendation of Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway.

2008 ◽  
Author(s):  
Hugues Abriel
Keyword(s):  
Cellular Pathway ◽  
Voltage Gated ◽  
Ankyrin G

scholarly journals Voltage-gated Nav channel targeting in the heart requires an ankyrin-G–dependent cellular pathway

2008 ◽  
Vol 180 (1) ◽  
pp. 173-186 ◽  
Author(s):  
John S. Lowe ◽  
Oleg Palygin ◽  
Naina Bhasin ◽  
Thomas J. Hund ◽  
Penelope A. Boyden ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Na Channel ◽  
Membrane Domains ◽  
Cellular Pathway ◽  
Channel Trafficking ◽  
Voltage Gated ◽  
Channel Current ◽  
Ankyrin G ◽  
Dependent Activity ◽  
Nav Channels

Voltage-gated Nav channels are required for normal electrical activity in neurons, skeletal muscle, and cardiomyocytes. In the heart, Nav1.5 is the predominant Nav channel, and Nav1.5-dependent activity regulates rapid upstroke of the cardiac action potential. Nav1.5 activity requires precise localization at specialized cardiomyocyte membrane domains. However, the molecular mechanisms underlying Nav channel trafficking in the heart are unknown. In this paper, we demonstrate that ankyrin-G is required for Nav1.5 targeting in the heart. Cardiomyocytes with reduced ankyrin-G display reduced Nav1.5 expression, abnormal Nav1.5 membrane targeting, and reduced Na+ channel current density. We define the structural requirements on ankyrin-G for Nav1.5 interactions and demonstrate that loss of Nav1.5 targeting is caused by the loss of direct Nav1.5–ankyrin-G interaction. These data are the first report of a cellular pathway required for Nav channel trafficking in the heart and suggest that ankyrin-G is critical for cardiac depolarization and Nav channel organization in multiple excitable tissues.

Abstract 1073: Cardiac Voltage-gated Nav channel Na v 1.5 Requires An AnkyrinG-dependent Pathway For Targeting in Cardiomyocytes

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
John S Lowe ◽  
Oleg Palygin ◽  
Patrick Wright ◽  
Erwin Shibata ◽  
Peter Mohler
Keyword(s):  
Ion Channels ◽  
Site Directed Mutagenesis ◽  
Loss Of Function ◽  
Excitable Cells ◽  
Membrane Expression ◽  
Voltage Gated ◽  
Ankyrin G ◽  
Ankyrin B ◽  
Dependent Pathway

Membrane localization of ion channels is very important for normal function in excitable cells. In heart, voltage-gated Na + channels are necessary for the rapid upstroke of the cardiomyocyte action potential, and variants in SCN5A (encodes Na v 1.5) are associated with fatal arrhythmias. We have identified ankyrin family proteins as critical components for normal ion channel and transporter targeting in cardiomyocytes. Humans with ANK2 (encodes ankyrin-B) loss of function variants display abnormal cardiac phenotypes and risk for sudden cardiac death. Mice that lack ankyrin-B expression display a similar phenotype. Our most recent results demonstrate that a second ankyrin gene product, ankyrin-G (encoded by ANK 3) is critical for targeting Na v 1.5 to specific cardiomyocyte membrane domains. We assessed the hypothesis that Na v 1.5 membrane expression and localization is controlled by an ankyrin-G-dependent pathway and disruption of ankyrin-G/Na v 1.5 interactions lead to human cardiac disease in this study. We used a combination of techniques including biochemistry, confocal microscopy, lentiviral expression, and electrophysiology to evaluate the functional relationship between ankyrin-G and Na v 1.5. We defined the structural elements on ankyrin-G and Na v 1.5 for their interaction using site-directed mutagenesis and in vitro binding assays. Lentiviral expression of shRNA targeted to rat 190 kD ankyrin-G effectively reduced the expression of ankyrin-G with a concomitant reduction of Na v 1.5 in immunofluorescence and immunoblot assays. Further-more, primary cardiomyocytes with reduced ankyrin-G expression have a significant reduction in Na + current density with no evident biophysical effects on Ca 2+ current or inactivation-gating of Na v 1.5 These results confirm the importance of ankyrin polypeptides for normal cardiac function and shed new light on the importance of intracellular trafficking pathways for the delivery and stability of critical ion channels and transporters in excitable cells.

scholarly journals Ankyrin-G Directly Binds to Kinesin-1 to Transport Voltage-Gated Na+ Channels into Axons

2014 ◽  
Vol 28 (2) ◽  
pp. 117-131 ◽  
Author(s):  
Joshua Barry ◽  
Yuanzheng Gu ◽  
Peter Jukkola ◽  
Brian O’Neill ◽  
Howard Gu ◽  
...  
Keyword(s):  
Na Channels ◽  
Voltage Gated ◽  
Ankyrin G

scholarly journals Tetrodotoxin-resistant voltage-gated sodium channel Nav 1.8 constitutively interacts with ankyrin G

2014 ◽  
Vol 131 (1) ◽  
pp. 33-41 ◽  
Author(s):  
Audrey Montersino ◽  
Anna Brachet ◽  
Géraldine Ferracci ◽  
Marie-Pierre Fache ◽  
Stephanie Angles d'Ortoli ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Ankyrin G

scholarly journals Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments

2001 ◽  
Vol 155 (5) ◽  
pp. 739-746 ◽  
Author(s):  
Scott M. Jenkins ◽  
Vann Bennett
Keyword(s):  
Adhesion Molecules ◽  
Sodium Channels ◽  
Action Potentials ◽  
Membrane Skeleton ◽  
Purkinje Neuron ◽  
Voltage Gated ◽  
Ankyrin G ◽  
Voltage Gated Sodium Channels ◽  
Cerebellar Purkinje Neurons ◽  
Axon Initial Segments

The axon initial segment is an excitable membrane highly enriched in voltage-gated sodium channels that integrates neuronal inputs and initiates action potentials. This study identifies Nav1.6 as the voltage-gated sodium channel isoform at mature Purkinje neuron initial segments and reports an essential role for ankyrin-G in coordinating the physiological assembly of Nav1.6, βIV spectrin, and the L1 cell adhesion molecules (L1 CAMs) neurofascin and NrCAM at initial segments of cerebellar Purkinje neurons. Ankyrin-G and βIV spectrin appear at axon initial segments by postnatal day 2, whereas L1 CAMs and Nav1.6 are not fully assembled at continuous high density along axon initial segments until postnatal day 9. L1 CAMs and Nav1.6 therefore do not initiate protein assembly at initial segments. βIV spectrin, Nav1.6, and L1 CAMs are not clustered in adult Purkinje neuron initial segments of mice lacking cerebellar ankyrin-G. These results support the conclusion that ankyrin-G coordinates the physiological assembly of a protein complex containing transmembrane adhesion molecules, voltage-gated sodium channels, and the spectrin membrane skeleton at axon initial segments.

scholarly journals βIV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier

2002 ◽  
Vol 156 (2) ◽  
pp. 337-348 ◽  
Author(s):  
Masayuki Komada ◽  
Philippe Soriano
Keyword(s):  
Sodium Channels ◽  
Embryonic Stem ◽  
Nodes Of Ranvier ◽  
Gene Trapping ◽  
Voltage Gated ◽  
Ankyrin G ◽  
Membrane Cytoskeleton ◽  
Voltage Gated Sodium Channels ◽  
Axon Initial Segments ◽  
Sodium Channel Clustering

β-Spectrin and ankyrin are major components of the membrane cytoskeleton. We have generated mice carrying a null mutation in the βIV-spectrin gene using gene trapping in embryonic stem cells. Mice homozygous for the mutation exhibit tremors and contraction of hindlimbs. βIV-spectrin expression is mostly restricted to neurons, where it colocalizes with and binds to ankyrin-G at axon initial segments (AISs) and nodes of Ranvier (NR). In βIV-spectrin–null neurons, neither ankyrin-G nor voltage-gated sodium channels (VGSC) are correctly clustered at these sites, suggesting that impaired action potential caused by mislocalization of VGSC leads to the phenotype. Conversely, in ankyrin-G–null neurons, βIV-spectrin is not localized to these sites. These results indicate that βIV-spectrin and ankyrin-G mutually stabilize the membrane protein cluster and the linked membrane cytoskeleton at AIS and NR.

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