A β(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice.
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.
Hund
Thomas J
TJ
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. thomas-hund@uiowa.edu
Koval
Olha M
OM
Li
Jingdong
J
Wright
Patrick J
PJ
Qian
Lan
L
Snyder
Jedidiah S
JS
Gudmundsson
Hjalti
H
Kline
Crystal F
CF
Davidson
Nathan P
NP
Cardona
Natalia
N
Rasband
Matthew N
MN
Anderson
Mark E
ME
Mohler
Peter J
PJ
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*
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