Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals.
In neurons, voltage-gated sodium channel beta subunits regulate the expression levels, subcellular localization, and electrophysiological properties of sodium channel alpha subunits. However, the contribution of beta subunits to sodium channel function in heart is poorly understood. We examined the role of beta1 in cardiac excitability using Scn1b null mice. Compared to wildtype mice, electrocardiograms recorded from Scn1b null mice displayed longer RR intervals and extended QT(c) intervals, both before and after autonomic block. In acutely dissociated ventricular myocytes, loss of beta1 expression resulted in a approximately 1.6-fold increase in both peak and persistent sodium current while channel gating and kinetics were unaffected. Na(v)1.5 expression increased in null myocytes approximately 1.3-fold. Action potential recordings in acutely dissociated ventricular myocytes showed slowed repolarization, supporting the extended QT(c) interval. Immunostaining of individual myocytes or ventricular sections revealed no discernable alterations in the localization of sodium channel alpha or beta subunits, ankyrin(B), ankyrin(G), N-cadherin, or connexin-43. Together, these results suggest that beta1 is critical for normal cardiac excitability and loss of beta1 may be associated with a long QT phenotype.
Lopez-Santiago
Luis F
LF
Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109-0632, USA.
Meadows
Laurence S
LS
Ernst
Sara J
SJ
Chen
Chunling
C
Malhotra
Jyoti Dhar
JD
McEwen
Dyke P
DP
Speelman
Audrey
A
Noebels
Jeffrey L
JL
Maier
Sebastian K G
SK
Lopatin
Anatoli N
AN
Isom
Lori L
LL
D000818:Animals; D001921:Brain / Q000502:physiology; D004562:Electrocardiography; D006321:Heart / Q000502:physiology; D006339:Heart Rate / Q000235:genetics* / Q000502:physiology; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000172:deficiency* / Q000502:physiology; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
C524974:Scn1b protein, mouse; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit