title: A β(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice.
abstract: Ion channel function is fundamental to the existence of life. In metazoans, the coordinate activities of voltage-gated Na(+) channels underlie cellular excitability and control neuronal communication, cardiac excitation-contraction coupling, and skeletal muscle function. However, despite decades of research and linkage of Na(+) channel dysfunction with arrhythmia, epilepsy, and myotonia, little progress has been made toward understanding the fundamental processes that regulate this family of proteins. Here, we have identified β(IV)-spectrin as a multifunctional regulatory platform for Na(+) channels in mice. We found that β(IV)-spectrin targeted critical structural and regulatory proteins to excitable membranes in the heart and brain. Animal models harboring mutant β(IV)-spectrin alleles displayed aberrant cellular excitability and whole animal physiology. Moreover, we identified a regulatory mechanism for Na(+) channels, via direct phosphorylation by β(IV)-spectrin-targeted calcium/calmodulin-dependent kinase II (CaMKII). Collectively, our data define an unexpected but indispensable molecular platform that determines membrane excitability in the mouse heart and brain.
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. thomas-hund@uiowa.edu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: Jingdong
authors.initials: J
authors.lastname: Li
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Wright
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.forename: Jedidiah S
authors.initials: JS
authors.lastname: Snyder
authors.forename: Hjalti
authors.initials: H
authors.lastname: Gudmundsson
authors.forename: Crystal F
authors.initials: CF
authors.lastname: Kline
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Davidson
authors.forename: Natalia
authors.initials: N
authors.lastname: Cardona
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Rasband
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002352:Carrier Proteins / Q000032:analysis; D006321:Heart / Q000502:physiology*; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010766:Phosphorylation; D015398:Signal Transduction; D015222:Sodium Channels / Q000378:metabolism; D013049:Spectrin / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; C504042:betaIV spectrin, mouse; D013049:Spectrin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium