Open-Channel Block by the Cytoplasmic Tail of Sodium Channel β4 as a Mechanism for Resurgent Sodium Current

Grieco, Tina M.; Malhotra, Jyoti; Chen, Chunling; Isom, Lori L.; Raman, Indira M.

doi:10.1016/j.neuron.2004.12.035

Cited by 214 publications

(331 citation statements)

References 45 publications

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“…Consistent with previous studies of Scn1b null hippocampal and cerebellar Purkinje neurons [12,26], no significant differences were detected in the voltage-dependence of sodium channel activation or inactivation (Fig. 2B), time-course of inactivation (Fig.…”

Section: Loss Of β1 Does Not Alter Sodium Channel Voltage-dependence supporting

confidence: 92%

“…Interestingly, results from acutely isolated Scn1b null hippocampal and cerebellar neurons, which express primarily TTX-S channels, showed none of these effects [12,26], suggesting that the physiological roles of β1 may be cell type specific and, importantly, that heterologous expression systems cannot mimic the situation in neurons. Previous studies describing the effects of β1 on TTX-R Na v 1.5 in vitro have yielded variable results, depending on the heterologous expression system utilized.…”

Section: Discussionmentioning

confidence: 99%

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Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

Lopez-Santiago

Meadows

Ernst

et al. 2007

Journal of Molecular and Cellular Cardiology

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168

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In neurons, voltage-gated sodium channel β subunits regulate the expression levels, subcellular localization, and electrophysiological properties of sodium channel α subunits. However, the contribution of β subunits to sodium channel function in heart is poorly understood. We examined the role of β1 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 β1 expression resulted in a ~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 ~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 α or β subunits, ankyrin B , ankyrin G , N-cadherin, or connexin-43. Together, these results suggest that β1 is critical for normal cardiac excitability and loss of β1 may be associated with a long QT phenotype.

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Section: Loss Of β1 Does Not Alter Sodium Channel Voltage-dependence supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

Lopez-Santiago

Meadows

Ernst

et al. 2007

Journal of Molecular and Cellular Cardiology

Self Cite

124

168

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“…3 B and C). A peptide corresponding to the cytoplasmic domain of β4 mediates resurgent current in Purkinje neurons in vitro, implicating β4 in this mechanism (33). β4 protein levels were unchanged in Scn1b null cerebella, suggesting that the reduced resurgent I Na in Scn1b null CGNs was not due to altered β4 expression (Fig.…”

Section: Resultsmentioning

confidence: 86%

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Brackenbury

Chen

Miyazaki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-gated Na + channel (VGSC) β1 subunits regulate cell-cell adhesion and channel activity in vitro. We previously showed that β1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that β1-mediated neurite outgrowth requires Na + current (I Na ) mediated by Na v 1.6. In addition, β1 is required for highfrequency action potential firing. Transient I Na is unchanged in Scn1b (β1) null CGNs; however, the resurgent I Na , thought to underlie high-frequency firing in Na v 1.6-expressing cerebellar neurons, is reduced. The proportion of axon initial segments (AIS) expressing Na v 1.6 is reduced in Scn1b null cerebellar neurons. In place of Na v 1.6 at the AIS, we observed an increase in Na v 1.1, whereas Na v 1.2 was unchanged. This indicates that β1 is required for normal localization of Na v 1.6 at the AIS during the postnatal developmental switch to Na v 1.6-mediated high-frequency firing. In agreement with this, β1 is normally expressed with α subunits at the AIS of P14 CGNs. We propose reciprocity of function between β1 and Na v 1.6 such that β1-mediated neurite outgrowth requires Na v 1.6-mediated I Na , and Na v 1.6 localization and consequent high-frequency firing require β1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.V oltage-gated Na + channels (VGSCs), composed of one poreforming α subunit and two β subunits (1), are responsible for initiation and conduction of action potentials (APs) (2). Of the nine α subunits (3), Na v 1.1, Na v 1.2, and Na v 1.6 are found in the postnatal CNS (4, 5) where they display developmentally regulated expression patterns in specialized neuronal subcellular domains. For example, Na v 1.1 and Na v 1.2 are replaced during postnatal development at the axon initial segment (AIS) and nodes of Ranvier by Na v 1.6. Scn8a null mice display motor dysfunction, ataxia, and lethality by postnatal day (P) 21, suggesting that this developmental switch to Na v 1.6 expression in brain is critical (6, 7). Scn8a null retinal ganglion neurons display impaired excitability, demonstrating that Na v 1.6 is vital for high-frequency firing (8-10). Thus, VGSC-driven neuronal activity is important for proper CNS development, although the underlying mechanism(s) are not well understood.VGSC β1 subunits are multifunctional molecules that modulate channel kinetics and gating, regulate channel cell surface expression, and participate in cell-cell adhesion in vitro (11). Scn1b (β1) null mice are ataxic, experience spontaneous seizures, and exhibit a prolonged cardiac QT interval, demonstrating that β1 modulates electrical excitability in vivo (12, 13). Consistent with this, human mutations in SCN1B result in epilepsy and arrhythmia (14-21). As a member of the Ig superfamily of cell adhesion molecules (CAMs), β1 mediates cellular aggregation, cytoskeletal recruitment, and extracellular matrix interactio...

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“…These two goals are attained by the exploitation of two highly specialized ion channels (Akemann and Knopfel, 2006): i) a resurgent Na + channel with an extremely fast recovery from inactivation, due to an unusual mechanism based on a peptide-mediated channel block, identified as the β 4 subunit (Grieco et al, 2005) but also mimicked by an exogenously applied peptide toxin (Schiavon et al, 2006); ii) K + channels of a subfamily (Kv3 or KCNC), which have very fast activation and deactivation kinetics associated with a high threshold for activation (Rudy and McBain, 2001). These properties of Kv3 channels cause a very fast action potential repolarization followed by a brief afterhyperpolarization, which allows a rapid recovery of Na + channels from inactivation.…”

Section: Introductionmentioning

confidence: 99%

Properties and expression of Kv3 channels in cerebellar Purkinje cells

Sacco

Luca

Tempia

2006

Molecular and Cellular Neuroscience

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In cerebellar Purkinje cells, Kv3 potassium channels are indispensable for firing at high frequencies. In Purkinje cells from young mice (P4-P7), Kv3 currents, recorded in whole-cell in slices, activated at −30 mV, with rapid activation and deactivation kinetics, and they were partially blocked by blood depressing substance-I (BDS-I, 1 μM). At positive potentials, Kv3 currents were slowly but completely inactivating, while the recovery from inactivation was about eightfold slower, suggesting that a previous firing activity or a small change of the resting potential could in principle accumulate inactivated Kv3 channels, thereby finely tuning Kv3 current availability for subsequent action potentials. Single-cell RT-PCR analysis showed the expression by all Purkinje cells (n = 10 for each subunit) of Kv3.1, Kv3.3 and Kv3.4 mRNA, while Kv3.2 was not expressed. These results add to the framework for interpreting the physiological function and the molecular determinants of Kv3 currents in cerebellar Purkinje cells.

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Open-Channel Block by the Cytoplasmic Tail of Sodium Channel β4 as a Mechanism for Resurgent Sodium Current

Cited by 214 publications

References 45 publications

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Properties and expression of Kv3 channels in cerebellar Purkinje cells

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Open-Channel Block by the Cytoplasmic Tail of Sodium Channel β4 as a Mechanism for Resurgent Sodium Current

Cited by 214 publications

References 45 publications

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Properties and expression of Kv3 channels in cerebellar Purkinje cells

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Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth