Singular localization of sodium channel β4 subunit in unmyelinated fibres and its role in the striatum

Miyazaki, Haruko; Oyama, Fumitaka; Inoue, Ritsuko; Aosaki, Toshihiko; Abe, Takaya; Kanazawa, Hiroshi; Kino, Yoshihiro; Kurosawa, Masaru; Shimizu, Jun; Ogiwara, Ikuo; Yamakawa, Kazuhiro; Koshimizu, Yoshinori; Fujiyama, Fumino; Kaneko, Takeshi; Shimizu, Hideaki; Nagatomo, Katsuhiro; Yamada, Katsuya; Shimogori, Tomomi; Hattori, Nobutaka; Miura, Masami; Nukina, Nobuyuki

doi:10.1038/ncomms6525

Cited by 64 publications

(85 citation statements)

References 56 publications

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“…For example, we recently reported that sodium channel beta 4 subunit (Navβ4) is a major determinant of resurgent currents in DRG neurons (3). Our results were consistent with Central Nervous System (CNS) studies, which proposed the C-terminal sequence of this subunit acts as an open channel blocker (2, 21, 39). In particular, a region of 20 amino acids within the cytoplasmic C-terminal region (known as the β4 peptide) is predicted to be key for Navβ4 positive regulation of fast resurgent currents (57, 75).…”

Section: Introductionsupporting

confidence: 92%

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Barbosa

Xiao

Johnson

et al. 2016

Pflugers Arch - Eur J Physiol

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Nav1.6 and Nav1.6 mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6 mediated resurgent currents by isoforms of Fibroblast growth Factor Homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas, FHF2B enhances resurgent currents. Overall our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies.

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Section: Introductionsupporting

confidence: 92%

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Barbosa

Xiao

Johnson

et al. 2016

Pflugers Arch - Eur J Physiol

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“…Global deletion of Navβ4, however, may affect motor performance through other pathways. It has been reported, for example (Miyazaki et al, 2014), that loss of Navβ4 disrupts firing in medium spiny neurons of the striatum, which is also involved in action selection and motor control.…”

Section: Discussionmentioning

confidence: 99%

Loss of Navβ4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance

et al. 2017

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SUMMARY The resurgent component of voltage-gated Na+ (Nav) currents, INaR, has been suggested to provide the depolarizing drive for high frequency firing and to be generated by voltage-dependent Nav channel block (at depolarized potentials) and unblock (at hyperpolarized potentials) by the accessory Navβ4 subunit. To test these hypotheses, we examined the effects of the targeted deletion of Scn4b (Navβ4) on INaR and on repetitive firing in cerebellar Purkinje neurons. We show here that Scn4b−/− animals have deficits in motor coordination and balance and that firing rates in Scn4b−/− Purkinje neurons are markedly attenuated. Acute, in vivo shRNA-mediated “knockdown” of Navβ4 in adult Purkinje neurons also reduced spontaneous and evoked firing rates. Dynamic clamp-mediated addition of INaR partially rescued firing in Scn4b−/− Purkinje neurons. Voltage-clamp experiments revealed that INaR was reduced (by ~50%), but not eliminated, in Scn4b−/− Purkinje neurons, revealing that additional mechanisms contribute to generation of INaR.

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“…compound, frozen by dry ice-cooled ethanol and then cut using cryostat. 15-μm-thick sections were autoclaved for antigen retrieval and immunostained as described previously40. We used following primary antibodies for immunostaining: rabbit polyclonal anti-human C-terminal AMCase at 1:1,000 dilution and goat polyclonal anti-Pepsin C at 1:500 dilutions.…”

Section: Methodsmentioning

confidence: 99%

Acidic mammalian chitinase is a proteases-resistant glycosidase in mouse digestive system

Ohno

Kimura

Miyazaki

et al. 2016

Sci Rep

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Chitinases are enzymes that hydrolyze chitin, a polymer of β-1, 4-linked N-acetyl-D-glucosamine (GlcNAc). Chitin has long been considered as a source of dietary fiber that is not digested in the mammalian digestive system. Here, we provide evidence that acidic mammalian chitinase (AMCase) can function as a major digestive enzyme that constitutively degrades chitin substrates and produces (GlcNAc)2 fragments in the mouse gastrointestinal environment. AMCase was resistant to endogenous pepsin C digestion and remained active in the mouse stomach extract at pH 2.0. The AMCase mRNA levels were much higher than those of four major gastric proteins and two housekeeping genes and comparable to the level of pepsinogen C in the mouse stomach tissues. Furthermore, AMCase was expressed in the gastric pepsinogen-synthesizing chief cells. The enzyme was also stable and active in the presence of trypsin and chymotrypsin at pH 7.6, where pepsin C was completely degraded. Mouse AMCase degraded polymeric colloidal and crystalline chitin substrates in the gastrointestinal environments in presence of the proteolytic enzymes. Thus, AMCase can function as a protease-resistant major glycosidase under the conditions of stomach and intestine and degrade chitin substrates to produce (GlcNAc)2, a source of carbon, nitrogen and energy.

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Singular localization of sodium channel β4 subunit in unmyelinated fibres and its role in the striatum

Cited by 64 publications

References 56 publications

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Loss of Navβ4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance

Acidic mammalian chitinase is a proteases-resistant glycosidase in mouse digestive system

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