Cytoskeletal protein 4.1R affects repolarization and regulates calcium handling in the heart.
The 4.1 proteins are a family of multifunctional adaptor proteins. They promote the mechanical stability of plasma membranes by interaction with the cytoskeletal proteins spectrin and actin and are required for the cell surface expression of a number of transmembrane proteins. Protein 4.1R is expressed in heart and upregulated in deteriorating human heart failure, but its functional role in myocardium is unknown. To investigate the role of protein 4.1R on myocardial contractility and electrophysiology, we studied 4.1R-deficient (knockout) mice (4.1R KO). ECG analysis revealed reduced heart rate with prolonged Q-T interval in 4.1R KO. No changes in ejection fraction and fractional shortening, assessed by echocardiography, were found. The action potential duration in isolated ventricular myocytes was prolonged in 4.1R KO. Ca(2+) transients were larger and slower to decay in 4.1R KO. The sarcoplasmic reticulum Ca(2+) content and Ca(2+) sparks frequency were increased. The Na(+)/Ca(2+) exchanger current density was reduced in 4.1R KO. The transient inward current inactivation was faster and the persistent Na(+) current density was increased in the 4.1R KO group, with possible effects on action potential duration. Although no major morphological changes were noted, 4.1R KO hearts showed reduced expression of NaV1.5alpha and increased expression of protein 4.1G. Our data indicate an unexpected and novel role for the cytoskeletal protein 4.1R in modulating the functional properties of several cardiac ion transporters with consequences on cardiac electrophysiology and with possible significant roles during normal cardiac function and disease.
Stagg
Mark A
MA
Heart Science Centre, National Heart & Lung Institute, Imperial College London, United Kingdom.
Carter
Edward
E
Sohrabi
Nadia
N
Siedlecka
Urszula
U
Soppa
Gopal K
GK
Mead
Fiona
F
Mohandas
Narla
N
Taylor-Harris
Pamela
P
Baines
Anthony
A
Bennett
Pauline
P
Yacoub
Magdi H
MH
Pinder
Jennifer C
JC
Terracciano
Cesare M N
CM
D000200:Action Potentials; D000818:Animals; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004452:Echocardiography; D004562:Electrocardiography; D006339:Heart Rate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013318:Stroke Volume; D013997:Time Factors; D016277:Ventricular Function, Left
D001798:Blood Proteins; C514956:Epb41 protein, mouse; D008840:Microfilament Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D002118:Calcium