Kinetic and functional analysis of transient, persistent and resurgent sodium currents in rat cerebellar granule cells <i>in situ</i>: an electrophysiological and modelling study

Magistretti, Jacopo; Castelli, Loretta; Forti, Lia; D’Angelo, Egidio

doi:10.1113/jphysiol.2006.106682

Cited by 80 publications

(110 citation statements)

References 46 publications

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“…3, Table 2). The "transient inward current" (corresponding to a fast Na ϩ current) (Magistretti et al, 2006) was significantly smaller in slow-spiking PrP 0/0 compared with fast-spiking (either wild-type or PrP 0/0 ) granule cells and reached its inward peak at higher potentials (Fig. 3C).…”

Section: Resultsmentioning

confidence: 97%

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

et al. 2008

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Section: Resultsmentioning

confidence: 97%

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

et al. 2008

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“…Changes in Na channels that reduce resurgent current disrupt repetitive firing by Purkinje neurons (14,15), and resurgent current is likewise proposed to facilitate spiking by granule cells (28). We therefore tested whether knockdown of Na V β4 altered the excitability of cultured granule cells.…”

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confidence: 99%

Control of transient, resurgent, and persistent current by open-channel block by Na channel β4 in cultured cerebellar granule neurons

Bant

Raman

2010

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

111

149

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Voltage-gated Na channels in several classes of neurons, including cells of the cerebellum, are subject to an open-channel block and unblock by an endogenous protein. The Na V β4 (Scn4b) subunit is a candidate blocking protein because a free peptide from its cytoplasmic tail, the β4 peptide, can block open Na channels and induce resurgent current as channels unblock upon repolarization. In heterologous expression systems, however, Na V β4 fails to produce resurgent current. We therefore tested the necessity of this subunit in generating resurgent current, as well as its influence on Na channel gating and action potential firing, by studying cultured cerebellar granule neurons treated with siRNA targeted against Scn4b. Knockdown of Scn4b, confirmed with quantitative RT-PCR, led to five electrophysiological phenotypes: a loss of resurgent current, a reduction of persistent current, a hyperpolarized half-inactivation voltage of transient current, a higher rheobase, and a decrease in repetitive firing. All disruptions of Na currents and firing were rescued by the β4 peptide. The simplest interpretation is that Na V β4 itself blocks Na channels of granule cells, making this subunit the first blocking protein that is responsible for resurgent current. The results also demonstrate that a known open-channel blocking peptide not only permits a rapid recovery from nonconducting states upon repolarization from positive voltages but also increases Na channel availability at negative potentials by antagonizing fast inactivation. Thus, Na V β4 expression determines multiple aspects of Na channel gating, thereby regulating excitability in cultured cerebellar granule cells., one of four β subunits of voltage-gated Na channels (1), is implicated in several pathologies: Na V β4 is down-regulated in Huntington's disease (2), cleaved by enzymes activated in Alzheimer's Disease (3), and mutated in some long-QT syndromes (4), raising the question of how it modulates Na currents in neurons and other cells. Among the proposed roles for Na V β4, based on studies of a peptide fragment of its cytoplasmic tail, is that it may act as an open-channel blocker of Na channels in neurons that produce resurgent current, i.e., reopening of Na channels upon repolarization from positive voltages (5).Resurgent current is present in several neuronal classes, including cell types in the cerebellum, brainstem, subthalamic nuclei, and dorsal root ganglia (6-11). As in other cells, voltage-gated Na channels in these neurons are closed at negative voltages and open upon depolarization. After opening, however, channels are blocked rapidly by an endogenous protein that prevents the fast inactivation gate from binding. Upon repolarization, this blocker is expelled, and resurgent current flows as channels reopen before either inactivating or deactivating, depending on the voltage (12). In Purkinje cells, modeling studies (13,14) and experiments on Na V 1.6 mutant mice, in which resurgent currents are reduced (14-16), have led to the proposal that Na channels t...

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“…TSC signaling is conserved from Drosophila to humans; for example, the Drosophila orthologs of the mammalian tuberous sclerosis proteins, dTSC1 and dTSC2, function downstream of the insulin receptor to regulate mTOR signals and cell size (14). Differentiation of the SOP cell into the ESO results from multiple asymmetric divisions that depend on differential regulation of Notch signaling to ultimately give rise to the differentiated ESO, which is comprised of an external bristle cell and socket cell as well as an internal sensory neuron and sheath cell (Figure 2A) (15). This process begins when the primary progenitor (pI) cell undergoes an asymmetric cell division to give rise to an anterior pIIb cell and a posterior pIIa cell.…”

Section: New Roles For Notch In Tuberous Sclerosismentioning

confidence: 99%

“…In cells with resurgent sodium current, depolarizing current flows as channels recover from inactivation, thereby promoting the firing of a second action potential, and such cells tend to fire bursts of closely spaced action potentials. A small, but growing, list of neurons is known to express resurgent sodium current, including cerebellar Purkinje neurons (9), subthalamic nucleus neurons (12), deep cerebellar nuclei neurons (13), cerebellar granule neurons (13)(14)(15), mesencephalic trigeminal motor neurons (16), vestibular nucleus neurons (17), and a subpopulation of primary sensory neurons in dorsal root ganglia (DRG; ref. 18).…”

Section: Figurementioning

confidence: 99%

Sodium channels gone wild: resurgent current from neuronal and muscle channelopathies

Cannon¹,

Bean²

2010

J. Clin. Invest.

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Voltage-dependent sodium channels are the central players in the excitability of neurons, cardiac muscle, and skeletal muscle. Hundreds of mutations in sodium channels have been associated with human disease, particularly genetic forms of epilepsy, arrhythmias, myotonia, and periodic paralysis. In this issue of the JCI, Jarecki and colleagues present evidence suggesting that many such mutations alter the gating of sodium channels to produce resurgent sodium current, an unusual form of gating in which sodium channels reopen following an action potential, thus promoting the firing of another action potential (see the related article beginning on page 369). The results of this study suggest a widespread pathophysiological role for this mechanism, previously described to occur normally in only a few types of neurons.

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Kinetic and functional analysis of transient, persistent and resurgent sodium currents in rat cerebellar granule cells in situ: an electrophysiological and modelling study

Cited by 80 publications

References 46 publications

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

Control of transient, resurgent, and persistent current by open-channel block by Na channel β4 in cultured cerebellar granule neurons

Sodium channels gone wild: resurgent current from neuronal and muscle channelopathies

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